Cancer-Associated Fibroblasts: Heterogeneity, Cancer Pathogenesis, and Therapeutic Targets

Abstract

Cancer-associated fibroblasts (CAFs) are functionally diverse stromal regulators that orchestrate tumor progression, metastasis, and therapy resistance through dynamic crosstalk within the tumor microenvironment (TME). Recent advances in single-cell multiomics and spatial transcriptomics have identified conserved CAF subtypes with distinct molecular signatures, spatial distributions, and context-dependent roles, highlighting their dual capacity to promote immunosuppression or restrain tumor growth. However, therapeutic strategies struggle to reconcile this functional duality, hindering clinical translation. This review systematically categorizes CAF subtypes by origin, biomarkers, and TME-specific functions, focusing on their roles in chemoresistance, maintenance of stemness, and formation of immunosuppressive niches. We evaluate emerging targeting approaches, including selective depletion of tumor-promoting subsets (e.g., fibroblast activation protein+ CAFs), epigenetic reprogramming toward antitumor phenotypes, and inhibition of CXCL12/CXCR4 or transforming growth factor-beta signaling pathways. Spatial multiomics-driven combinatorial therapies, such as the synergistic use of CAFs and immune checkpoint inhibitors, are highlighted as strategies to overcome microenvironment-driven resistance. By integrating CAF biology with translational advances, this work provides a roadmap for developing subtype-specific biomarkers and precision stromal therapies, directly informing efforts to disrupt tumor-stroma coevolution. Key concepts include spatial transcriptomics, stromal reprogramming, and tumor-stroma coevolution, offering actionable insights for both mechanistic research and clinical innovation.

Keywords

cancer-associated fibroblasts / heterogeneity / pathogenesis / theranostic / tumor microenvironment

References

[1] R. L. Siegel, A. N. Giaquinto, A. Jemal, “Cancer Statistics, 2024,” CA: A Cancer Journal for Clinicians 74 (2024): 12-49.

[2] R. Kalluri, “The Biology and Function of Fibroblasts in Cancer,” Nature Reviews Cancer 16 (2016): 582-598.

[3] G. Friedman, O. Levi-Galibov, E. David, et al., “Cancer-associated Fibroblast Compositions Change With Breast Cancer Progression Linking the Ratio of S100A4(+) and PDPN(+) CAFs to Clinical Outcome,” Nature Cancer 1 (2020): 692-708.

[4] C. Ganier, P. Mazin, G. Herrera-Oropeza, et al., “Multiscale Spatial Mapping of Cell Populations Across Anatomical Sites in Healthy human Skin and Basal Cell Carcinoma,” PNAS 121 (2024): e2313326120.

[5] N. Chalkidi, M.-T. Melissari, A. Henriques, A. Stavropoulou, G. Kollias, V. Koliaraki, “Activation and Functions of Col6a1+ Fibroblasts in Colitis-Associated Cancer,” International Journal of Molecular Sciences 25 (2023): 148.

[6] M. Song, J. He, Q.-Z. Pan, et al., “Cancer-Associated Fibroblast-Mediated Cellular Crosstalk Supports Hepatocellular Carcinoma Progression,” Hepatology 73 (2021): 1717-1735.

[7] N. Niu, X. Shen, Z. Wang, et al., “Tumor Cell-intrinsic Epigenetic Dysregulation Shapes Cancer-associated Fibroblasts Heterogeneity to Metabolically Support Pancreatic Cancer,” Cancer Cell 42 (2024): 869-884. e869.

[8] J. A. Grout, P. Sirven, A. M. Leader, et al., “Spatial Positioning and Matrix Programs of Cancer-Associated Fibroblasts Promote T-cell Exclusion in Human Lung Tumors,” Cancer Discovery 12 (2022): 2606-2625.

[9] H. Zheng, M. An, Y. Luo, et al., “PDGFRα(+)ITGA11(+) Fibroblasts Foster Early-stage Cancer Lymphovascular Invasion and Lymphatic Metastasis via ITGA11-SELE Interplay,” Cancer Cell 42 (2024): 682-700, e612.

[10] S. Bhattacharjee, F. Hamberger, A. Ravichandra, et al., “Tumor Restriction by Type I Collagen Opposes Tumor-promoting Effects of Cancer-associated Fibroblasts,” Journal of Clinical Investigation 131 (2021): e146987.

[11] E. Elyada, M. Bolisetty, P. Laise, et al., “Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts,” Cancer Discovery 9 (2019): 1102-1123.

[12] G. Mucciolo, J. AraosHenríquez, M. Jihad, et al., “EGFR-activated Myofibroblasts Promote Metastasis of Pancreatic Cancer,” Cancer Cell 42 (2024): 101-118. e111.

[13] X. Li, Z. Sun, G. Peng, et al., “Single-cell RNA Sequencing Reveals a Pro-invasive Cancer-associated Fibroblast Subgroup Associated With Poor Clinical Outcomes in Patients With Gastric Cancer,” Theranostics 12 (2022): 620-638.

[14] X. Zhang, S. Zheng, C. Hu, et al., “Cancer-associated Fibroblast-induced lncRNA UPK1A-AS1 Confers Platinum Resistance in Pancreatic Cancer via Efficient Double-strand Break Repair,” Oncogene 41 (2022): 2372-2389.

[15] D. Kerdidani, E. Aerakis, K.-M. Verrou, et al., “Lung Tumor MHCII Immunity Depends on in Situ Antigen Presentation by Fibroblasts,” Journal of Experimental Medicine 219 (2022): e20210815.

[16] T.-L. Zhang, C. Xia, B.-W. Zheng, et al., “Integrating Single-cell and Spatial Transcriptomics Reveals Endoplasmic Reticulum Stress-related CAF Subpopulations Associated With Chordoma Progression,” Neuro-Oncology 26 (2024): 295-308.

[17] C. Miao, L. Liu, Y. Cao, et al., “OSCC-derived EVs Educate Fibroblasts and Remodel Collagen Landscape,” Matrix Biology 134 (2024): 132-143.

[18] C. Quemerais, C. Jean, A. Brunel, et al., “Unveiling FKBP7 as an Early Endoplasmic Reticulum Sentinel in Pancreatic Stellate Cell Activation, Collagen Remodeling and Tumor Progression,” Cancer Letters 614 (2025): 217538.

[19] H. Huang, Z. Wang, Y. Zhang, et al., “Mesothelial Cell-derived Antigen-presenting Cancer-associated Fibroblasts Induce Expansion of Regulatory T Cells in Pancreatic Cancer,” Cancer Cell 40 (2022): 656-673. e657.

[20] H. Hu, Z. Piotrowska, P. J. Hare, et al., “Three Subtypes of Lung Cancer Fibroblasts Define Distinct Therapeutic Paradigms,” Cancer Cell 39 (2021): 1531-1547. e1510.

[21] A. Costa, Y. Kieffer, A. Scholer-Dahirel, et al., “Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer,” Cancer Cell 33 (2018): 463-479. e410.

[22] Y. Kieffer, H. R. Hocine, G. Gentric, et al., “Single-Cell Analysis Reveals Fibroblast Clusters Linked to Immunotherapy Resistance in Cancer,” Cancer Discovery 10 (2020): 1330-1351.

[23] J. W. Eun, J. H. Yoon, H. R. Ahn, et al., “Cancer-associated Fibroblast-derived Secreted Phosphoprotein 1 Contributes to Resistance of Hepatocellular Carcinoma to Sorafenib and Lenvatinib,” Cancer Commun (London) 43 (2023): 455-479.

[24] W. Huang, L. Zhang, M. Yang, et al., “Cancer-associated Fibroblasts Promote the Survival of Irradiated Nasopharyngeal Carcinoma Cells via the NF-κB Pathway,” Journal of Experimental & Clinical Cancer Research 40 (2021): 87.

[25] T. Bertero, W. M. Oldham, E. M. Grasset, et al., “Tumor-Stroma Mechanics Coordinate Amino Acid Availability to Sustain Tumor Growth and Malignancy,” Cell Metabolism 29 (2019): 124-140. e110.

[26] M. Wehrli, S. Guinn, F. Birocchi, et al., “Mesothelin CAR T Cells Secreting Anti-FAP/Anti-CD3 Molecules Efficiently Target Pancreatic Adenocarcinoma and Its Stroma,” Clinical Cancer Research 30 (2024): 1859-1877.

[27] R. Sakemura, M. Hefazi, E. L. Siegler, et al., “Targeting Cancer-associated Fibroblasts in the Bone Marrow Prevents Resistance to CART-cell Therapy in Multiple Myeloma,” Blood 139 (2022): 3708-3721.

[28] G. Biffi, T. E. Oni, B. Spielman, et al., “IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma,” Cancer Discovery 9 (2019): 282-301.

[29] R. Melchionna, P. Trono, A. DiCarlo, F. DiModugno, P. Nisticò, “Transcription Factors in Fibroblast Plasticity and CAF Heterogeneity,” Journal of Experimental & Clinical Cancer Research 42 (2023): 347.

[30] D. Lavie, A. Ben-Shmuel, N. Erez, R. Scherz-Shouval, “Cancer-associated Fibroblasts in the Single-cell Era,” Nat Cancer 3 (2022): 793-807.

[31] X. Geng, H. Chen, L. Zhao, et al., “Cancer-Associated Fibroblast (CAF) Heterogeneity and Targeting Therapy of CAFs in Pancreatic Cancer,” Frontiers in Cell and Developmental Biology 9 (2021): 655152.

[32] L. Arpinati, G. Carradori, R. Scherz-Shouval, “CAF-induced Physical Constraints Controlling T Cell state and Localization in Solid Tumours,” Nature Reviews Cancer 24 (2024): 676-693.

[33] R. Seifert, I. L. Alberts, A. Afshar-Oromieh, K. Rahbar, “Prostate Cancer Theranostics: PSMA Targeted Therapy,” PET Clinics 16 (2021): 391-396.

[34] Q. Lecocq, Y. De Vlaeminck, H. Hanssens, et al., “Theranostics in Immuno-oncology Using Nanobody Derivatives,” Theranostics 9 (2019): 7772-7791.

[35] A. K. Buck, S. E. Serfling, T. Lindner, et al., “CXCR4-targeted Theranostics in Oncology,” European Journal of Nuclear Medicine and Molecular Imaging 49 (2022): 4133-4144.

[36] P. Barcellos-De-Souza, G. Comito, C. Pons-Segura, et al., “Mesenchymal Stem Cells Are Recruited and Activated Into Carcinoma-Associated Fibroblasts by Prostate Cancer Microenvironment-Derived TGF-β1,” Stem Cells 34 (2016): 2536-2547.

[37] S. Werner, J. Lützkendorf, T. Müller, L. P. Müller, G. Posern, “MRTF-A Controls Myofibroblastic Differentiation of human Multipotent Stromal Cells and Their Tumour-supporting Function in Xenograft Models,” Scientific Reports 9 (2019): 11725.

[38] C. E. Weber, A. N. Kothari, P. Y. Wai, et al., “Osteopontin Mediates an MZF1-TGF-β1-dependent Transformation of Mesenchymal Stem Cells Into Cancer-associated Fibroblasts in Breast Cancer,” Oncogene 34 (2015): 4821-4833.

[39] K. Louault, T. Porras, M.-H. Lee, et al., “Fibroblasts and Macrophages Cooperate to Create a Pro-tumorigenic and Immune Resistant Environment via Activation of TGF-β/IL-6 Pathway in Neuroblastoma,” Oncoimmunology 11 (2022): 2146860.

[40] K. Louault, L. Blavier, M.-H. Lee, et al., “Nuclear Factor-κB Activation by Transforming Growth Factor-β1 Drives Tumour Microenvironment-mediated Drug Resistance in Neuroblastoma,” British Journal of Cancer 131 (2024): 90-100.

[41] S. Gottschling, M. Granzow, R. Kuner, et al., “Mesenchymal Stem Cells in Non-small Cell Lung Cancer-different From Others? Insights From Comparative Molecular and Functional Analyses,” Lung Cancer 80 (2013): 19-29.

[42] L. Shangguan, X. Ti, U. Krause, et al., “Inhibition of TGF-β/Smad Signaling by BAMBI Blocks Differentiation of human Mesenchymal Stem Cells to Carcinoma-associated Fibroblasts and Abolishes Their Protumor Effects,” Stem Cells 30 (2012): 2810-2819.

[43] Y. Shi, L. Du, L. Lin, Y. Wang, “Tumour-associated Mesenchymal Stem/Stromal Cells: Emerging Therapeutic Targets,” Nature Reviews Drug Discovery 16 (2017): 35-52.

[44] E. M. Zeisberg, S. Potenta, L. Xie, M. Zeisberg, R. Kalluri, “Discovery of Endothelial to Mesenchymal Transition as a Source for Carcinoma-associated Fibroblasts,” Cancer Research 67 (2007): 10123-10128.

[45] S. Piera-Velazquez, S. A. Jimenez, “Endothelial to Mesenchymal Transition: Role in Physiology and in the Pathogenesis of Human Diseases,” Physiological Reviews 99 (2019): 1281-1324.

[46] M. Manetti, E. Romano, I. Rosa, et al., “Endothelial-to-mesenchymal Transition Contributes to Endothelial Dysfunction and Dermal Fibrosis in Systemic Sclerosis,” Annals of the Rheumatic Diseases 76 (2017): 924-934.

[47] Y. Fang, M. Chen, G. Li, et al., “Cancer-associated Fibroblast-Like Fibroblasts in Vocal Fold Leukoplakia Suppress CD8(+)T Cell Functions by Inducing IL-6 Autocrine Loop and Interacting With Th17 Cells,” Cancer Letters 546 (2022): 215839.

[48] S. Itoh, “The Transcriptional co-activator P/CAF Potentiates TGF-beta/Smad Signaling,” Nucleic Acids Research 28 (2000): 4291-4298.

[49] Z. Chen, Y. Gao, P. Zhang, et al., “Identification of Gastric Cancer Stem Cells With CD44 and Lgr5 Double Labelling and Their Initial Roles on Gastric Cancer Malignancy and Chemotherapy Resistance,” Cell Biology and Toxicology 41 (2024): 12.

[50] A. Børretzen, K. Gravdal, S. A. Haukaas, et al., “The Epithelial-mesenchymal Transition Regulators Twist, Slug, and Snail Are Associated With Aggressive Tumour Features and Poor Outcome in Prostate Cancer Patients,” The Journal of Pathology: Clinical Research 7 (2021): 253-270.

[51] J. Du, B. Sun, X. Zhao, et al., “Hypoxia Promotes Vasculogenic Mimicry Formation by Inducing Epithelial-mesenchymal Transition in Ovarian Carcinoma,” Gynecologic Oncology 133 (2014): 575-583.

[52] N. Clere, S. Renault, I. Corre, “Endothelial-to-Mesenchymal Transition in Cancer,” Frontiers in Cell and Developmental Biology 8 (2020): 747.

[53] K.-W. Lee, S.-Y. Yeo, J.-R. Gong, et al., “PRRX1 is a Master Transcription Factor of Stromal Fibroblasts for Myofibroblastic Lineage Progression,” Nature Communications 13 (2022): 2793.

[54] A. Filliol, R. F. Schwabe, “Contributions of Fibroblasts, Extracellular Matrix, Stiffness, and Mechanosensing to Hepatocarcinogenesis,” Seminars in Liver Disease 39 (2019): 315-333.

[55] H. Luo, X. Xia, L.-B. Huang, et al., “Pan-cancer Single-cell Analysis Reveals the Heterogeneity and Plasticity of Cancer-associated Fibroblasts in the Tumor Microenvironment,” Nature Communications 13 (2022): 6619.

[56] C. Hu, R. Xia, X. Zhang, et al., “circFARP1 enables Cancer-associated Fibroblasts to Promote Gemcitabine Resistance in Pancreatic Cancer via the LIF/STAT3 Axis,” Molecular Cancer 21 (2022): 24.

[57] S. Furuhashi, M. A. Bustos, S. Mizuno, et al., “Spatial Profiling of Cancer-associated Fibroblasts of Sporadic Early Onset Colon Cancer Microenvironment,” NPJ Precision Oncology 7 (2023): 118.

[58] X. Pan, J. Zhou, Q. Xiao, et al., “Cancer-associated Fibroblast Heterogeneity Is Associated With Organ-specific Metastasis in Pancreatic Ductal Adenocarcinoma,” Journal of Hematology & Oncology 14 (2021): 184.

[59] M. A. Eckert, F. Coscia, A. Chryplewicz, et al., “Proteomics Reveals NNMT as a Master Metabolic Regulator of Cancer-associated Fibroblasts,” Nature 569 (2019): 723-728.

[60] X. Zhang, M. Zhang, H. Sun, et al., “The Role of Transcription Factors in the Crosstalk Between Cancer-associated Fibroblasts and Tumor Cells,” Journal of Advanced Research 67 (2025): 121-132.

[61] Z. Wang, “CAF Heterogeneity and Dynamics,” Nature Cell Biology 24 (2022): 1686.

[62] S. Affo, A. Nair, F. Brundu, et al., “Promotion of Cholangiocarcinoma Growth by Diverse Cancer-associated Fibroblast Subpopulations,” Cancer Cell 39 (2021): 866-882. e811.

[63] J. M. Houthuijzen, R. De Bruijn, E. Van Der Burg, et al., “CD26-negative and CD26-positive Tissue-resident Fibroblasts Contribute to Functionally Distinct CAF Subpopulations in Breast Cancer,” Nature Communications 14 (2023): 183.

[64] J. Ye, J. M. Baer, D. V. Faget, et al., “Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression,” Cancer Discovery 14 (2024): 1302-1323.

[65] J. I. Belle, D. Sen, J. M. Baer, et al., “Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer,” Cancer Discovery 14 (2024): 1324-1355.

[66] Z. Ou, L. Zhu, X. Chen, et al., “Hypoxia-Induced Senescent Fibroblasts Secrete IGF1 to Promote Cancer Stemness in Esophageal Squamous Cell Carcinoma,” Cancer Research 85, no. 6 (2024): 1064-1081.

[67] E. Strating, M. P. Verhagen, E. Wensink, et al., “Co-cultures of Colon Cancer Cells and Cancer-associated Fibroblasts Recapitulate the Aggressive Features of Mesenchymal-Like Colon Cancer,” Frontiers in Immunology 14 (2023): 1053920.

[68] Y. Ma, J. Zhu, S. Chen, et al., “Activated Gastric Cancer-associated Fibroblasts Contribute to the Malignant Phenotype and 5-FU Resistance via Paracrine Action in Gastric Cancer,” Cancer Cell International 18 (2018): 104.

[69] A. Herrera, M. Herrera, L. Alba-Castellón, et al., “Protumorigenic Effects of Snail-expression Fibroblasts on Colon Cancer Cells,” International Journal of Cancer 134 (2014): 2984-2990.

[70] C. Chen, Q. Guo, Y. Liu, et al., “Single-cell and Spatial Transcriptomics Reveal POSTN(+) Cancer-associated Fibroblasts Correlated With Immune Suppression and Tumour Progression in Non-small Cell Lung Cancer,” Clinical and Translational Medicine 13 (2023): e1515.

[71] C. Ma, C. Yang, Ai Peng, et al., “Pan-cancer Spatially Resolved Single-cell Analysis Reveals the Crosstalk Between Cancer-associated Fibroblasts and Tumor Microenvironment,” Molecular Cancer 22 (2023): 170.

[72] L. Cords, S. Tietscher, T. Anzeneder, et al., “Cancer-associated Fibroblast Classification in Single-cell and Spatial Proteomics Data,” Nature Communications 14 (2023): 4294.

[73] P. C.-T. Tang, J. Y.-F. Chung, V. W.-W. Xue, et al., “Smad3 Promotes Cancer-Associated Fibroblasts Generation via Macrophage-Myofibroblast Transition,” Advanced Science (Weinheim) 9 (2022): e2101235.

[74] S. Jain, J. W. Rick, R. S. Joshi, et al., “Single-cell RNA Sequencing and Spatial Transcriptomics Reveal Cancer-associated Fibroblasts in Glioblastoma With Protumoral Effects,” Journal of Clinical Investigation 133 (2023): e147087.

[75] S. Ferri-Borgogno, Y. Zhu, J. Sheng, et al., “Spatial Transcriptomics Depict Ligand-Receptor Cross-talk Heterogeneity at the Tumor-Stroma Interface in Long-Term Ovarian Cancer Survivors,” Cancer Research 83 (2023): 1503-1516.

[76] S. Parte, A. B. Kaur, R. K. Nimmakayala, et al., “Cancer-Associated Fibroblast Induces Acinar-to-Ductal Cell Transdifferentiation and Pancreatic Cancer Initiation via LAMA5/ITGA4 Axis,” Gastroenterology 166 (2024): 842-858. e845.

[77] D. S. Foster, M. Januszyk, D. Delitto, et al., “Multiomic Analysis Reveals Conservation of Cancer-associated Fibroblast Phenotypes Across Species and Tissue of Origin,” Cancer Cell 40 (2022): 1392-1406. e1397.

[78] P. M. Galbo, A. T. Madsen, Y. Liu, et al., “Functional Contribution and Clinical Implication of Cancer-Associated Fibroblasts in Glioblastoma,” Clinical Cancer Research 30 (2024): 865-876.

[79] M. Papanicolaou, A. L. Parker, M. Yam, et al., “Temporal Profiling of the Breast Tumour Microenvironment Reveals Collagen XII as a Driver of Metastasis,” Nature Communications 13 (2022): 4587.

[80] X. Mao, J. Xu, W. Wang, et al., “Crosstalk Between Cancer-associated Fibroblasts and Immune Cells in the Tumor Microenvironment: New Findings and Future Perspectives,” Molecular Cancer 20 (2021): 131.

[81] A. Giguelay, E. Turtoi, L. Khelaf, et al., “The Landscape of Cancer-associated Fibroblasts in Colorectal Cancer Liver Metastases,” Theranostics 12 (2022): 7624-7639.

[82] Z. Pan, T. Xu, L. Bao, et al., “CREB3L1 promotes Tumor Growth and Metastasis of Anaplastic Thyroid Carcinoma by Remodeling the Tumor Microenvironment,” Molecular Cancer 21 (2022): 190.

[83] X. Liu, J. Li, X. Yang, et al., “Carcinoma-associated Fibroblast-derived Lysyl Oxidase-rich Extracellular Vesicles Mediate Collagen Crosslinking and Promote Epithelial-mesenchymal Transition via p-FAK/p-paxillin/YAP Signaling,” International Journal of Oral Science 15 (2023): 32.

[84] S. Zhang, L. Yuan, L. Danilova, et al., “Spatial Transcriptomics Analysis of Neoadjuvant Cabozantinib and nivolumab in Advanced Hepatocellular Carcinoma Identifies Independent Mechanisms of Resistance and Recurrence,” Genome Medicine 15 (2023): 72.

[85] H. Kobayashi, K. A. Gieniec, T. R. M. Lannagan, et al., “The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis,” Gastroenterology 162 (2022): 890-906.

[86] E. D. Wrenn, A. A. Apfelbaum, E. R. Rudzinski, et al., “Cancer-Associated Fibroblast-Like Tumor Cells Remodel the Ewing Sarcoma Tumor Microenvironment,” Clinical Cancer Research 29 (2023): 5140-5154.

[87] D. DelRio, I. Masi, V. Caprara, et al., “The β-arrestin1/Endothelin Axis Bolsters Ovarian Fibroblast-dependent Invadosome Activity and Cancer Cell Metastatic Potential,” Cell Death & Disease 15 (2024): 358.

[88] D. Song, Y. Wu, J. Li, et al., “Insulin-Like Growth Factor 2 Drives Fibroblast-mediated Tumor Immunoevasion and Confers Resistance to Immunotherapy,” Journal of Clinical Investigation 134 (2024): e183366.

[89] C. Li, T. Chen, J. Liu, et al., “FGF19-Induced Inflammatory CAF Promoted Neutrophil Extracellular Trap Formation in the Liver Metastasis of Colorectal Cancer,” Advanced Science (Weinheim) 10 (2023): e2302613.

[90] D. Yu, H. Xu, J. Zhou, K. Fang, Z. Zhao, Ke Xu, “PDPN/CCL2/STAT3 Feedback Loop Alter CAF Heterogeneity to Promote Angiogenesis in Colorectal Cancer,” Angiogenesis 27 (2024): 809-825.

[91] Q. Liao, H. Shi, J. Yang, et al., “FTO Elicits Tumor Neovascularization in Cancer-associated Fibroblasts Through Eliminating M(6)A Modifications of Multiple Pro-angiogenic Factors,” Cancer Letters 592 (2024): 216911.

[92] B. Liu, B. Zhang, J. Qi, et al., “Targeting MFGE8 Secreted by Cancer-associated Fibroblasts Blocks Angiogenesis and Metastasis in Esophageal Squamous Cell Carcinoma,” PNAS 120 (2023): e2307914120.

[93] A. T. Krishnamurty, J. A. Shyer, M. Thai, et al., “LRRC15(+) myofibroblasts Dictate the Stromal Setpoint to Suppress Tumour Immunity,” Nature 611 (2022): 148-154.

[94] H. Wang, J. Chen, X. Chen, et al., “Cancer-Associated Fibroblasts Expressing Sulfatase 1 Facilitate VEGFA-Dependent Microenvironmental Remodeling to Support Colorectal Cancer,” Cancer Research 84 (2024): 3371-3387.

[95] I. I. Verginadis, H. Avgousti, J. Monslow, et al., “A Stromal Integrated Stress Response Activates Perivascular Cancer-associated Fibroblasts to Drive Angiogenesis and Tumour Progression,” Nature Cell Biology 24 (2022): 940-953.

[96] L. Cords, S. Engler, M. Haberecker, et al., “Cancer-associated Fibroblast Phenotypes Are Associated With Patient Outcome in Non-small Cell Lung Cancer,” Cancer Cell 42 (2024): 396-412. e395.

[97] H. Croizer, R. Mhaidly, Y. Kieffer, et al., “Deciphering the Spatial Landscape and Plasticity of Immunosuppressive Fibroblasts in Breast Cancer,” Nature Communications 15 (2024): 2806.

[98] D. J. Agorku, A. Bosio, F. Alves, P. Ströbel, O. Hardt, “Colorectal Cancer-associated Fibroblasts Inhibit Effector T Cells via NECTIN2 Signaling,” Cancer Letters 595 (2024): 216985.

[99] M. Licaj, R. Mhaidly, Y. Kieffer, et al., “Residual ANTXR1+ Myofibroblasts After Chemotherapy Inhibit Anti-tumor Immunity via YAP1 Signaling Pathway,” Nature Communications 15 (2024): 1312.

[100] Y. Cheng, X. Chen, Li Feng, et al., “Stromal Architecture and Fibroblast Subpopulations With Opposing Effects on Outcomes in Hepatocellular Carcinoma,” Cell Discovery 11 (2025).

[101] T. Pellinen, L. Paavolainen, A. Martín-Bernabé, et al., “Fibroblast Subsets in Non-small Cell Lung Cancer: Associations With Survival, Mutations, and Immune Features,” JNCI: Journal of the National Cancer Institute 115 (2023): 71-82.

[102] B. H. Jenkins, I. Tracy, M. F. S. D. Rodrigues, et al., “Single Cell and Spatial Analysis of Immune-hot and Immune-cold Tumours Identifies Fibroblast Subtypes Associated With Distinct Immunological Niches and Positive Immunotherapy Response,” Molecular Cancer 24 (2025): 3.

[103] R. D. Schreiber, L. J. Old, M. J. Smyth, “Cancer Immunoediting: Integrating Immunity's Roles in Cancer Suppression and Promotion,” Science 331 (2011): 1565-1570.

[104] K. Nakamura, M. J. Smyth, “Myeloid Immunosuppression and Immune Checkpoints in the Tumor Microenvironment,” Cellular & Molecular Immunology 17 (2020): 1-12.

[105] Y. Liu, C. Li, Y. Lu, C. Liu, W. Yang, “Tumor Microenvironment-mediated Immune Tolerance in Development and Treatment of Gastric Cancer,” Frontiers in Immunology 13 (2022): 1016817.

[106] K. Li, H. Shi, B. Zhang, et al., “Myeloid-derived Suppressor Cells as Immunosuppressive Regulators and Therapeutic Targets in Cancer,” Signal Transduction and Targeted Therapy 6 (2021): 362.

[107] C. Chen, Z. Wang, Y. Ding, Y. Qin, “Tumor Microenvironment-mediated Immune Evasion in Hepatocellular Carcinoma,” Frontiers in Immunology 14 (2023): 1133308.

[108] K. B. Kennel, M. Bozlar, A. F. De Valk, F. R. Greten, “Cancer-Associated Fibroblasts in Inflammation and Antitumor Immunity,” Clinical Cancer Research 29 (2023): 1009-1016.

[109] H. Zhang, X. Yue, Z. Chen, et al., “Define Cancer-associated Fibroblasts (CAFs) in the Tumor Microenvironment: New Opportunities in Cancer Immunotherapy and Advances in Clinical Trials,” Molecular Cancer 22 (2023): 159.

[110] L. Jenkins, U. Jungwirth, A. Avgustinova, et al., “Cancer-Associated Fibroblasts Suppress CD8+ T-cell Infiltration and Confer Resistance to Immune-Checkpoint Blockade,” Cancer Research 82 (2022): 2904-2917.

[111] G. L. Szeto, S. D. Finley, “Integrative Approaches to Cancer Immunotherapy,” Trends in Cancer 5 (2019): 400-410.

[112] R. Rui, L. Zhou, S. He, “Cancer Immunotherapies: Advances and Bottlenecks,” Frontiers in Immunology 14 (2023): 1212476.

[113] J. H. Cha, L. C. Chan, M. S. Song, M. C. Hung, “New Approaches on Cancer Immunotherapy,” Cold Spring Harbor Perspectives in Medicine 10 (2020): a036863.

[114] S. Wen, Y. Hou, L. Fu, et al., “Cancer-associated Fibroblast (CAF)-derived IL32 Promotes Breast Cancer Cell Invasion and Metastasis via Integrin β3-p38 MAPK Signalling,” Cancer Letters 442 (2019): 320-332.

[115] D. Peng, M. Fu, M. Wang, Y. Wei, X. Wei, “Targeting TGF-β Signal Transduction for Fibrosis and Cancer Therapy,” Molecular Cancer 21 (2022): 104.

[116] K. Pang, Z.-D. Shi, L-Ya Wei, et al., “Research Progress of Therapeutic Effects and Drug Resistance of Immunotherapy Based on PD-1/PD-L1 Blockade,” Drug Resistance Updates 66 (2023): 100907.

[117] Y. Jiang, M. Chen, H. Nie, Y. Yuan, “PD-1 and PD-L1 in Cancer Immunotherapy: Clinical Implications and Future Considerations,” Human Vaccines & Immunotherapeutics 15 (2019): 1111-1122.

[118] Y. Han, D. Liu, L. Li, “PD-1/PD-L1 Pathway: Current Researches in Cancer,” American Journal of Cancer Research 10 (2020): 727-742.

[119] C. Ghosh, G. Luong, Y. Sun, “A Snapshot of the PD-1/PD-L1 Pathway,” Journal of Cancer 12 (2021): 2735-2746.

[120] M. Wu, Q. Huang, Y. Xie, et al., “Improvement of the Anticancer Efficacy of PD-1/PD-L1 Blockade via Combination Therapy and PD-L1 Regulation,” Journal of Hematology & Oncology 15 (2022): 24.

[121] X. Liu, L. Yang, X. Tan, “PD-1/PD-L1 Pathway: A Double-edged Sword in Periodontitis,” Biomedicine & Pharmacotherapy 159 (2023): 114215.

[122] J. G. Egen, M. S. Kuhns, J. P. Allison, “CTLA-4: New Insights Into Its Biological Function and Use in Tumor Immunotherapy,” Nature Immunology 3 (2002): 611-618.

[123] F. S. Hodi, S. J. O'Day, D. F. Mcdermott, et al., “Improved Survival With ipilimumab in Patients With Metastatic Melanoma,” New England Journal of Medicine 363 (2010): 711-723.

[124] K. Kawasaki, K. Noma, T. Kato, et al., “PD-L1-expressing Cancer-associated Fibroblasts Induce Tumor Immunosuppression and Contribute to Poor Clinical Outcome in Esophageal Cancer,” Cancer Immunology, Immunotherapy 72 (2023): 3787-3802.

[125] K. Teramoto, T. Igarashi, Y. Kataoka, et al., “Clinical Significance of PD-L1-positive Cancer-associated Fibroblasts in pN0M0 Non-small Cell Lung Cancer,” Lung Cancer 137 (2019): 56-63.

[126] Q. Zhang, J. Wang, J. Zhang, Y. Wang, Y. Wang, F. Liu, “Cancer-associated Fibroblasts-induced Remodeling of Tumor Immune Microenvironment via Jagged1 in Glioma,” Cell. Signalling 115 (2024): 111016.

[127] B. Lim, Y. Lin, N. Navin, “Advancing Cancer Research and Medicine With Single-Cell Genomics,” Cancer Cell 37 (2020): 456-470.

[128] N. Kim, H. K. Kim, K. Lee, et al., “Single-cell RNA Sequencing Demonstrates the Molecular and Cellular Reprogramming of Metastatic Lung Adenocarcinoma,” Nature Communications 11 (2020): 2285.

[129] D. Sugiyama, K. Hinohara, H. Nishikawa, “Significance of Regulatory T Cells in Cancer Immunology and Immunotherapy,” Experimental Dermatology 32 (2023): 256-263.

[130] A. Sica, M. Massarotti, “Myeloid Suppressor Cells in Cancer and Autoimmunity,” Journal of Autoimmunity 85 (2017): 117-125.

[131] S. Kumagai, K. Itahashi, H. Nishikawa, “Regulatory T Cell-mediated Immunosuppression Orchestrated by Cancer: Towards an Immuno-genomic Paradigm for Precision Medicine,” Nature Reviews Clinical Oncology 21 (2024): 337-353.

[132] K. Okła, “Myeloid-Derived Suppressor Cells (MDSCs) in Ovarian Cancer-Looking Back and Forward,” Cells 12 (2023): 1912.

[133] J. Medina-Echeverz, T. Eggert, M. Han, T. F. Greten, “Hepatic Myeloid-derived Suppressor Cells in Cancer,” Cancer Immunology, Immunotherapy 64 (2015): 931-940.

[134] C. Groth, X. Hu, R. Weber, et al., “Immunosuppression Mediated by Myeloid-derived Suppressor Cells (MDSCs) During Tumour Progression,” British Journal of Cancer 120 (2019): 16-25.

[135] E. Azizi, A. J. Carr, G. Plitas, et al., “Single-Cell Map of Diverse Immune Phenotypes in the Breast Tumor Microenvironment,” Cell 174 (2018): 1293-1308. e1236.

[136] M. De Simone, A. Arrigoni, G. Rossetti, et al., “Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells,” Immunity 45 (2016): 1135-1147.

[137] G. Plitas, C. Konopacki, K. Wu, et al., “Regulatory T Cells Exhibit Distinct Features in Human Breast Cancer,” Immunity 45 (2016): 1122-1134.

[138] T. Saito, H. Nishikawa, H. Wada, et al., “Two FOXP3(+)CD4(+) T Cell Subpopulations Distinctly Control the Prognosis of Colorectal Cancers,” Nature Medicine 22 (2016): 679-684.

[139] D. V. Sawant, H. Yano, M. Chikina, et al., “Adaptive Plasticity of IL-10(+) and IL-35(+) T(reg) Cells Cooperatively Promotes Tumor T Cell Exhaustion,” Nature Immunology 20 (2019): 724-735.

[140] J. B. Wing, A. Tanaka, S. Sakaguchi, “Human FOXP3(+) Regulatory T Cell Heterogeneity and Function in Autoimmunity and Cancer,” Immunity 50 (2019): 302-316.

[141] A. Varveri, M. Papadopoulou, Z. Papadovasilakis, et al., “Immunological Synapse Formation Between T Regulatory Cells and Cancer-associated Fibroblasts Promotes Tumour Development,” Nature Communications 15 (2024): 4988.

[142] R. A. O'Connor, B. R. Martinez, L. Koppensteiner, L. Mathieson, A. R. Akram , “Cancer-associated Fibroblasts Drive CXCL13 Production in Activated T Cells via TGF-beta,” Frontiers in Immunology 14 (2023): 1221532.

[143] Y. Lu, H. Li, P. Zhao, et al., “Crosstalk Between Cancer-associated Fibroblasts and Non-neuroendocrine Tumor Cells in Small Cell Lung Cancer Involves in Glycolysis and Antigen-presenting Features,” Molecular Medicine 30 (2024): 274.

[144] X. Zhao, L. Ding, Z. Lu, et al., “Diminished CD68(+) Cancer-Associated Fibroblast Subset Induces Regulatory T-Cell (Treg) Infiltration and Predicts Poor Prognosis of Oral Squamous Cell Carcinoma Patients,” American Journal of Pathology 190 (2020): 886-899.

[145] S. Pei, J. Sjölund, Y. Pan, K. Pietras, M. C. I. Karlsson, “Cancer-associated Fibroblasts Express CD1d and Activate Invariant Natural Killer T Cells Under Cellular Stress,” Cellular & Molecular Immunology 21 (2024): 91-94.

[146] D. I. Godfrey, J. LeNours, D. M. Andrews, A. P. Uldrich, J. Rossjohn, “Unconventional T Cell Targets for Cancer Immunotherapy,” Immunity 48 (2018): 453-473.

[147] S. Hegde, A. M. Leader, M. Merad, “MDSC: Markers, Development, States, and Unaddressed Complexity,” Immunity 54 (2021): 875-884.

[148] G.-Q. Zhu, Z. Tang, R. Huang, et al., “CD36(+) cancer-associated Fibroblasts Provide Immunosuppressive Microenvironment for Hepatocellular Carcinoma via Secretion of Macrophage Migration Inhibitory Factor,” Cell Discovery 9 (2023): 25.

[149] V. Kumar, L. Donthireddy, D. Marvel, et al., “Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors,” Cancer Cell 32 (2017): 654-668. e655.

[150] X. Yang, Y. Lin, Y. Shi, et al., “FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3-CCL2 Signaling,” Cancer Research 76 (2016): 4124-4135.

[151] H. Xiang, C. P. Ramil, J. Hai, et al., “Cancer-Associated Fibroblasts Promote Immunosuppression by Inducing ROS-Generating Monocytic MDSCs in Lung Squamous Cell Carcinoma,” Cancer Immunology Research 8 (2020): 436-450.

[152] A. Bianchi, I. De Castro Silva, N. U. Deshpande, et al., “Cell-Autonomous Cxcl1 Sustains Tolerogenic Circuitries and Stromal Inflammation via Neutrophil-Derived TNF in Pancreatic Cancer,” Cancer Discovery 13 (2023): 1428-1453.

[153] Q. Zhao, L. Huang, G. Qin, et al., “Cancer-associated Fibroblasts Induce Monocytic Myeloid-derived Suppressor Cell Generation via IL-6/Exosomal miR-21-activated STAT3 Signaling to Promote Cisplatin Resistance in Esophageal Squamous Cell Carcinoma,” Cancer Letters 518 (2021): 35-48.

[154] M. Kundu, R. Butti, V. K. Panda, et al., “Modulation of the Tumor Microenvironment and Mechanism of Immunotherapy-based Drug Resistance in Breast Cancer,” Molecular Cancer 23 (2024): 92.

[155] K. Khalaf, D. Hana, J. T.-T. Chou, C. Singh, A. Mackiewicz, M. Kaczmarek, “Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance,” Frontiers in Immunology 12 (2021): 656364.

[156] T. Akiyama, T. Yasuda, T. Uchihara, et al., “Stromal Reprogramming Through Dual PDGFRα/β Blockade Boosts the Efficacy of Anti-PD-1 Immunotherapy in Fibrotic Tumors,” Cancer Research 83 (2023): 753-770.

[157] C. Ngambenjawong, H. H. Gustafson, S. H. Pun, “Progress in Tumor-associated Macrophage (TAM)-targeted Therapeutics,” Advanced Drug Delivery Reviews 114 (2017): 206-221.

[158] D. G. De Nardo, B. Ruffell, “Macrophages as Regulators of Tumour Immunity and Immunotherapy,” Nature Reviews Immunology 19 (2019): 369-382.

[159] Y. Pan, Y. Yu, X. Wang, T. Zhang, “Tumor-Associated Macrophages in Tumor Immunity,” Frontiers in Immunology 11 (2020): 583084.

[160] N. Higashino, Y.-I. Koma, M. Hosono, et al., “Fibroblast Activation Protein-positive Fibroblasts Promote Tumor Progression Through Secretion of CCL2 and Interleukin-6 in Esophageal Squamous Cell Carcinoma,” Laboratory Investigation 99 (2019): 777-792.

[161] R. Allaoui, C. Bergenfelz, S. Mohlin, et al., “Cancer-associated Fibroblast-secreted CXCL16 Attracts Monocytes to Promote Stroma Activation in Triple-negative Breast Cancers,” Nature Communications 7 (2016): 13050.

[162] M. Augsten, C. Hägglöf, E. Olsson, et al., “CXCL14 is an Autocrine Growth Factor for Fibroblasts and Acts as a Multi-modal Stimulator of Prostate Tumor Growth,” PNAS 106 (2009): 3414-3419.

[163] B. Gok Yavuz, G. Gunaydin, M. E. Gedik, et al., “Cancer Associated Fibroblasts Sculpt Tumour Microenvironment by Recruiting Monocytes and Inducing Immunosuppressive PD-1(+) TAMs,” Scientific Reports 9 (2019): 3172.

[164] M. M. Markiewski, R. A. Deangelis, F. Benencia, et al., “Modulation of the Antitumor Immune Response by Complement,” Nature Immunology 9 (2008): 1225-1235.

[165] S. Davidson, M. Efremova, A. Riedel, et al., “Single-Cell RNA Sequencing Reveals a Dynamic Stromal Niche That Supports Tumor Growth,” Cell Reports 31 (2020): 107628.

[166] R. Zhang, F. Qi, F. Zhao, et al., “Cancer-associated Fibroblasts Enhance Tumor-associated Macrophages Enrichment and Suppress NK Cells Function in Colorectal Cancer,” Cell Death & Disease 10 (2019): 273.

[167] O. Shani, T. Vorobyov, L. Monteran, et al., “Fibroblast-Derived IL33 Facilitates Breast Cancer Metastasis by Modifying the Immune Microenvironment and Driving Type 2 Immunity,” Cancer Research 80 (2020): 5317-5329.

[168] S. Chen, Y. Morine, K. Tokuda, et al., “Cancer‑Associated Fibroblast‑Induced M2‑Polarized Macrophages Promote Hepatocellular Carcinoma Progression via the Plasminogen Activator Inhibitor‑1 Pathway,” International Journal of Oncology 59 (2021): 59.

[169] G. Comito, E. Giannoni, C. P. Segura, et al., “Cancer-associated Fibroblasts and M2-polarized Macrophages Synergize During Prostate Carcinoma Progression,” Oncogene 33 (2014): 2423-2431.

[170] Y. Zhao, S. Rahmy, Z. Liu, C. Zhang, X. Lu, “Rational Targeting of Immunosuppressive Neutrophils in Cancer,” Pharmacology & Therapeutics 212 (2020): 107556.

[171] T.-T. Wang, Y.-L. Zhao, L.-S. Peng, et al., “Tumour-activated Neutrophils in Gastric Cancer Foster Immune Suppression and Disease Progression Through GM-CSF-PD-L1 Pathway,” Gut 66 (2017): 1900-1911.

[172] E. Kolaczkowska, “Immunosuppressive Lung Neutrophils,” Blood 140 (2022): 802-803.

[173] Q. Hu, R. Wang, J. Zhang, Q. Xue, B. Ding, “Tumor-associated Neutrophils Upregulate PANoptosis to Foster an Immunosuppressive Microenvironment of Non-small Cell Lung Cancer,” Cancer Immunology, Immunotherapy 72 (2023): 4293-4308.

[174] F. Hajizadeh, L. AghebatiMaleki, M. Alexander, et al., “Tumor-associated Neutrophils as New Players in Immunosuppressive Process of the Tumor Microenvironment in Breast Cancer,” Life Sciences 264 (2021): 118699.

[175] K. Pelka, M. Hofree, J. H. Chen, et al., “Spatially Organized Multicellular Immune Hubs in human Colorectal Cancer,” Cell 184 (2021): 4734-4752. e4720.

[176] Z. Tan, C. Kan, M. Sun, et al., “Mapping Breast Cancer Microenvironment through Single-Cell Omics,” Frontiers in Immunology 13 (2022): 868813.

[177] K. S. S. Enfield, E. Colliver, C. Lee, et al., “Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer,” Cancer Discovery 14 (2024): 1018-1047.

[178] S. Zhang, W. Fang, S. Zhou, et al., “Single Cell Transcriptomic Analyses Implicate an Immunosuppressive Tumor Microenvironment in Pancreatic Cancer Liver Metastasis,” Nature Communications 14 (2023): 5123.

[179] R. Chandra, J. D. Karalis, C. Liu, et al., “The Colorectal Cancer Tumor Microenvironment and Its Impact on Liver and Lung Metastasis,” Cancers (Basel) 13 (2021): 6206.

[180] E. Batlle, J. Massagué, “Transforming Growth Factor-β Signaling in Immunity and Cancer,” Immunity 50 (2019): 924-940.

[181] W. Chen, “TGF-β Regulation of T Cells,” Annual Review of Immunology 41 (2023): 483-512.

[182] Z. Fang, Q. Meng, J. Xu, et al., “Signaling Pathways in Cancer-associated Fibroblasts: Recent Advances and Future Perspectives,” Cancer Commun (Lond) 43 (2023): 3-41.

[183] L. Li, J.-R. Wei, J. Dong, et al., “Laminin γ2-mediating T Cell Exclusion Attenuates Response to anti-PD-1 Therapy,” Science Advances 7 (2021): eabc8346.

[184] M. Ahmadzadeh, S. A. Rosenberg, “TGF-beta 1 Attenuates the Acquisition and Expression of Effector Function by Tumor Antigen-specific human Memory CD8 T Cells,” Journal of Immunology 174 (2005): 5215-5223.

[185] N. Shimasaki, A. Jain, D. Campana, “NK Cells for Cancer Immunotherapy,” Nature Reviews Drug Discovery 19 (2020): 200-218.

[186] J. A. Myers, J. S. Miller, “Exploring the NK Cell Platform for Cancer Immunotherapy,” Nature Reviews Clinical Oncology 18 (2021): 85-100.

[187] M. G. Morvan, L. L. Lanier, “NK Cells and Cancer: You Can Teach Innate Cells New Tricks,” Nature Reviews Cancer 16 (2016): 7-19.

[188] T. Bald, M. F. Krummel, M. J. Smyth, K. C. Barry, “The NK Cell-cancer Cycle: Advances and New Challenges in NK Cell-based Immunotherapies,” Nature Immunology 21 (2020): 835-847.

[189] G. Xie, H. Dong, Y. Liang, J. D. Ham, R. Rizwan, J. Chen, “CAR-NK Cells: A Promising Cellular Immunotherapy for Cancer,” EBioMedicine 59 (2020): 102975.

[190] A. Tejchman, N. Lamerant-Fayel, J.-C. Jacquinet, et al., “Tumor Hypoxia Modulates Podoplanin/CCL21 Interactions in CCR7+ NK Cell Recruitment and CCR7+ Tumor Cell Mobilization,” Oncotarget 8 (2017): 31876-31887.

[191] T. Li, Y. Yang, X. Hua, et al., “Hepatocellular Carcinoma-associated Fibroblasts Trigger NK Cell Dysfunction via PGE2 and IDO,” Cancer Letters 318 (2012): 154-161.

[192] M. Balsamo, F. Scordamaglia, G. Pietra, et al., “Melanoma-associated Fibroblasts Modulate NK Cell Phenotype and Antitumor Cytotoxicity,” PNAS 106 (2009): 20847-20852.

[193] Y. E. Lee, G.-Y. Go, E.-Y. Koh, et al., “Synergistic Therapeutic Combination With a CAF Inhibitor Enhances CAR-NK-mediated Cytotoxicity via Reduction of CAF-released IL-6,” Journal for ImmunoTherapy of Cancer 11 (2023): e006130.

[194] L. Yao, J. Hou, X. Wu, et al., “Cancer-associated Fibroblasts Impair the Cytotoxic Function of NK Cells in Gastric Cancer by Inducing Ferroptosis via Iron Regulation,” Redox Biology 67 (2023): 102923.

[195] S. Lee, B. Ricci, J. Tran, et al., “Stroma-derived Dickkopf-1 Contributes to the Suppression of NK Cell Cytotoxicity in Breast Cancer,” Nature Communications 16 (2025): 1183.

[196] A. Ben-Shmuel, Y. Gruper, C. Halperin, et al., “Cancer-associated Fibroblasts Serve as Decoys to Suppress NK Cell Anti-cancer Cytotoxicity in Breast Cancer,” Cancer Discovery 15, no. 6 (2025): 1247-1269.

[197] R. Francescone, D. BarbosaVendramini-Costa, J. Franco-Barraza, et al., “Netrin G1 Promotes Pancreatic Tumorigenesis Through Cancer-Associated Fibroblast-Driven Nutritional Support and Immunosuppression,” Cancer Discovery 11 (2021): 446-479.

[198] T. Inoue, K. Adachi, K. Kawana, et al., “Cancer-associated Fibroblast Suppresses Killing Activity of Natural Killer Cells Through Downregulation of Poliovirus Receptor (PVR/CD155), a Ligand of Activating NK Receptor,” International Journal of Oncology 49 (2016): 1297-1304.

[199] N. Yang, K. Lode, R. Berzaghi, A. Islam, I. Martinez-Zubiaurre, T. Hellevik, “Irradiated Tumor Fibroblasts Avoid Immune Recognition and Retain Immunosuppressive Functions over Natural Killer Cells,” Frontiers in Immunology 11 (2020): 602530.

[200] S. Patwardhan, P. Mahadik, O. Shetty, S. Sen, “ECM Stiffness-tuned Exosomes Drive Breast Cancer Motility Through Thrombospondin-1,” Biomaterials 279 (2021): 121185.

[201] X. Li, C. González-Maroto, M. Tavassoli, “Crosstalk Between CAFs and Tumour Cells in Head and Neck Cancer,” Cell Death Discovery 10 (2024): 303.

[202] C. Hu, Y. Zhang, C. Wu, Q. Huang, “Heterogeneity of Cancer-associated Fibroblasts in Head and Neck Squamous Cell Carcinoma: Opportunities and Challenges,” Cell Death Discovery 9 (2023): 124.

[203] A. Palumbo, N. MeirelesDaCosta, B. Pontes, et al., “Esophageal Cancer Development: Crucial Clues Arising From the Extracellular Matrix,” Cells 9 (2020): 455.

[204] A. N. Hosein, R. A. Brekken, A. Maitra, “Pancreatic Cancer Stroma: An Update on Therapeutic Targeting Strategies,” Nature reviews Gastroenterology & Hepatology 17 (2020): 487-505.

[205] X. Li, J. Pan, T. Liu, et al., “Novel TCF21(high) Pericyte Subpopulation Promotes Colorectal Cancer Metastasis by Remodelling Perivascular Matrix,” Gut 72 (2023): 710-721.

[206] H. Zhao, Z. Chen, Y. Fang, et al., “Prediction of Prognosis and Recurrence of Bladder Cancer by ECM-Related Genes,” Journal of Immunology Research 2022 (2022): 1793005.

[207] W. Zhang, L. Zhang, H. Dong, H. Peng, “TGIF2 is a Potential Biomarker for Diagnosis and Prognosis of Glioma,” Frontiers in Immunology 15 (2024): 1356833.

[208] A. L. Parker, E. Bowman, A. Zingone, et al., “Extracellular Matrix Profiles Determine Risk and Prognosis of the Squamous Cell Carcinoma Subtype of Non-small Cell Lung Carcinoma,” Genome Medicine 14 (2022): 126.

[209] Z. Yuan, Y. Li, S. Zhang, et al., “Extracellular Matrix Remodeling in Tumor Progression and Immune Escape: From Mechanisms to Treatments,” Molecular Cancer 22 (2023): 48.

[210] A. M. Roy, R. Iyer, S. Chakraborty, “The Extracellular Matrix in Hepatocellular Carcinoma: Mechanisms and Therapeutic Vulnerability,” Cell Reports Medicine 4 (2023): 101170.

[211] J. D. Martin, D. Fukumura, D. G. Duda, Y. Boucher, R. K. Jain, “Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity,” Cold Spring Harbor Perspectives in Medicine 6 (2016): a027094.

[212] L. Bao, H. Kong, Y. Ja, et al., “The Relationship Between Cancer and Biomechanics,” Frontiers in Oncology 13 (2023): 1273154.

[213] L. Caja, F. Dituri, S. Mancarella, et al., “TGF-β and the Tissue Microenvironment: Relevance in Fibrosis and Cancer,” International Journal of Molecular Sciences 19 (2018): 1294.

[214] C. Tian, K. R. Clauser, D. Öhlund, et al., “Proteomic Analyses of ECM During Pancreatic Ductal Adenocarcinoma Progression Reveal Different Contributions by Tumor and Stromal Cells,” PNAS 116 (2019): 19609-19618.

[215] A. Chakravarthy, L. Khan, N. P. Bensler, P. Bose, D. D. De Carvalho, “TGF-β-associated Extracellular Matrix Genes Link Cancer-associated Fibroblasts to Immune Evasion and Immunotherapy Failure,” Nature Communications 9 (2018): 4692.

[216] M. Egeblad, M. G. Rasch, V. M. Weaver, “Dynamic Interplay Between the Collagen Scaffold and Tumor Evolution,” Current Opinion in Cell Biology 22 (2010): 697-706.

[217] D. E. Kuczek, A. M. H. Larsen, M.-L. Thorseth, et al., “Collagen Density Regulates the Activity of Tumor-infiltrating T Cells,” Journal for ImmunoTherapy of Cancer 7 (2019): 68.

[218] M. Chirivì, F. Maiullari, M. Milan, et al., “Tumor Extracellular Matrix Stiffness Promptly Modulates the Phenotype and Gene Expression of Infiltrating T Lymphocytes,” International Journal of Molecular Sciences 22 (2021): 5862.

[219] A. D. Doyle, D. J. Sykora, G. G. Pacheco, M. L. Kutys, K. M. Yamada, “3D mesenchymal Cell Migration Is Driven by Anterior Cellular Contraction That Generates an Extracellular Matrix Prestrain,” Developmental Cell 56 (2021): 826-841. e824.

[220] Y. Attieh, A. G. Clark, C. Grass, et al., “Cancer-associated Fibroblasts Lead Tumor Invasion Through Integrin-β3-dependent Fibronectin Assembly,” Journal of Cell Biology 216 (2017): 3509-3520.

[221] O. De Wever, Q. D. Nguyen, L. Van Hoorde, et al., “Tenascin-C and SF/HGF Produced by Myofibroblasts in Vitro Provide Convergent Pro-invasive Signals to human Colon Cancer Cells Through RhoA and Rac,” Faseb Journal 18 (2004): 1016-1018.

[222] A. M. H. Larsen, D. E. Kuczek, A. Kalvisa, et al., “Collagen Density Modulates the Immunosuppressive Functions of Macrophages,” Journal of Immunology 205 (2020): 1461-1472.

[223] A. M. A. Rømer, M. L. Thorseth, D. H. Madsen, “Immune Modulatory Properties of Collagen in Cancer,” Frontiers in Immunology 12 (2021): 791453.

[224] Y. Chen, J. Kim, S. Yang, et al., “Type I Collagen Deletion in αSMA(+) Myofibroblasts Augments Immune Suppression and Accelerates Progression of Pancreatic Cancer,” Cancer Cell 39 (2021): 548-565. e546.

[225] C. Tian, Y. Huang, K. R. Clauser, et al., “Suppression of Pancreatic Ductal Adenocarcinoma Growth and Metastasis by Fibrillar Collagens Produced Selectively by Tumor Cells,” Nature Communications 12 (2021): 2328.

[226] B. W. Miller, J. P. Morton, M. Pinese, et al., “Targeting the LOX/Hypoxia Axis Reverses Many of the Features That Make Pancreatic Cancer Deadly: Inhibition of LOX Abrogates Metastasis and Enhances Drug Efficacy,” EMBO Molecular Medicine 7 (2015): 1063-1076.

[227] H. J. Wu, M. Hao, S. K. Yeo, J. L. Guan, “FAK Signaling in Cancer-associated Fibroblasts Promotes Breast Cancer Cell Migration and Metastasis by Exosomal miRNAs-mediated Intercellular Communication,” Oncogene 39 (2020): 2539-2549.

[228] X. Jin, Q. Deng, S. Ye, et al., “Cancer-associated Fibroblast-derived Periostin Promotes Papillary Thyroid Tumor Growth Through Integrin-FAK-STAT3 Signaling,” Theranostics 14 (2024): 3014-3028.

[229] J. Xie, X. Qi, Y. Wang, et al., “Cancer-associated Fibroblasts Secrete Hypoxia-induced Serglycin to Promote Head and Neck Squamous Cell Carcinoma Tumor Cell Growth in Vitro and in Vivo by Activating the Wnt/β-catenin Pathway,” Cellular Oncology (Dordrecht) 44 (2021): 661-671.

[230] A. Ries, D. Flehberger, A. Slany, et al., “Mesothelioma-associated Fibroblasts Enhance Proliferation and Migration of Pleural Mesothelioma Cells via c-Met/PI3K and WNT Signaling but Do Not Protect Against Cisplatin,” Journal of Experimental & Clinical Cancer Research 42 (2023): 27.

[231] Z. Ma, X. Li, Y. Mao, et al., “Interferon-dependent SLC14A1(+) Cancer-associated Fibroblasts Promote Cancer Stemness via WNT5A in Bladder Cancer,” Cancer Cell 40 (2022): 1550-1565. e1557.

[232] Z. Zhou, Q. Zhou, X. Wu, et al., “VCAM-1 Secreted From Cancer-associated Fibroblasts Enhances the Growth and Invasion of Lung Cancer Cells Through AKT and MAPK Signaling,” Cancer Letters 473 (2020): 62-73.

[233] M. Wessolly, E. Mairinger, S. Borchert, et al., “CAF-Associated Paracrine Signaling Worsens Outcome and Potentially Contributes to Chemoresistance in Epithelial Ovarian Cancer,” Frontiers in Oncology 12 (2022): 798680.

[234] L. Veghini, D. Pasini, R. Fang, et al., “Differential Activity of MAPK Signalling Defines Fibroblast Subtypes in Pancreatic Cancer,” Nature Communications 15 (2024): 10534.

[235] T. Nakanishi, Y.-I. Koma, S. Miyako, et al., “AREG Upregulation in Cancer Cells via Direct Interaction With Cancer-Associated Fibroblasts Promotes Esophageal Squamous Cell Carcinoma Progression through EGFR-Erk/p38 MAPK Signaling,” Cells 13 (2024): 1733.

[236] J. A. Tuxhorn, S. J. McAlhany, T. D. Dang, G. E. Ayala, D. R. Rowley, “Stromal Cells Promote Angiogenesis and Growth of human Prostate Tumors in a Differential Reactive Stroma (DRS) Xenograft Model,” Cancer Research 62 (2002): 3298-3307.

[237] A. Orimo, P. B. Gupta, D. C. Sgroi, et al., “Stromal Fibroblasts Present in Invasive human Breast Carcinomas Promote Tumor Growth and Angiogenesis Through Elevated SDF-1/CXCL12 Secretion,” Cell 121 (2005): 335-348.

[238] H. P. Gerber, J. Kowalski, D. Sherman, D. A. Eberhard, N. Ferrara, “Complete Inhibition of Rhabdomyosarcoma Xenograft Growth and Neovascularization Requires Blockade of both Tumor and Host Vascular Endothelial Growth Factor,” Cancer Research 60 (2000): 6253-6258.

[239] D. Fukumura, R. Xavier, T. Sugiura, et al., “Tumor Induction of VEGF Promoter Activity in Stromal Cells,” Cell 94 (1998): 715-725.

[240] Y. Crawford, I. Kasman, L. Yu, et al., “PDGF-C Mediates the Angiogenic and Tumorigenic Properties of Fibroblasts Associated With Tumors Refractory to Anti-VEGF Treatment,” Cancer Cell 15 (2009): 21-34.

[241] X. Wan, S. Guan, Y. Hou, et al., “FOSL2 promotes VEGF-independent Angiogenesis by Transcriptionnally Activating Wnt5a in Breast Cancer-associated Fibroblasts,” Theranostics 11 (2021): 4975-4991.

[242] K. Pietras, J. Pahler, G. Bergers, D. Hanahan, “Functions of Paracrine PDGF Signaling in the Proangiogenic Tumor Stroma Revealed by Pharmacological Targeting,” Plos Medicine 5 (2008): e19.

[243] C. Anderberg, H. Li, L. Fredriksson, et al., “Paracrine Signaling by Platelet-derived Growth Factor-CC Promotes Tumor Growth by Recruitment of Cancer-associated Fibroblasts,” Cancer Research 69 (2009): 369-378.

[244] X. Hou, A. Kumar, C. Lee, et al., “PDGF-CC Blockade Inhibits Pathological Angiogenesis by Acting on Multiple Cellular and Molecular Targets,” PNAS 107 (2010): 12216-12221.

[245] R. Kanzaki, S. Reid, P. Bolivar, et al., “FHL2 expression by Cancer-associated Fibroblasts Promotes Metastasis and Angiogenesis in Lung Adenocarcinoma,” International Journal of Cancer 156 (2025): 431-446.

[246] S. A. Patel, M. B. Nilsson, X. Le, T. Cascone, R. K. Jain, J. V. Heymach, “Molecular Mechanisms and Future Implications of VEGF/VEGFR in Cancer Therapy,” Clinical Cancer Research 29 (2023): 30-39.

[247] S. Kiri, T. Ryba, “Cancer, Metastasis, and the Epigenome,” Molecular Cancer 23 (2024): 154.

[248] J. Fares, M. Y. Fares, H. H. Khachfe, H. A. Salhab, Y. Fares, “Molecular Principles of Metastasis: A Hallmark of Cancer Revisited,” Signal Transduction and Targeted Therapy 5 (2020): 28.

[249] G. Z. Li, G. M. Doherty, J. Wang, “Surgical Management of Gastric Cancer: A Review,” JAMA Surgery 157 (2022): 446-454.

[250] R. E. Coleman, P. I. Croucher, A. R. Padhani, et al., “Bone Metastases,” Nature Reviews Disease Primers 6 (2020): 83.

[251] J. Chang, O. Chaudhuri, “Beyond Proteases: Basement Membrane Mechanics and Cancer Invasion,” Journal of Cell Biology 218 (2019): 2456-2469.

[252] A. Gaiko-Shcherbak, J. Eschenbruch, N. M. Kronenberg, et al., “Cell Force-Driven Basement Membrane Disruption Fuels EGF- and Stiffness-Induced Invasive Cell Dissemination From Benign Breast Gland Acini,” International Journal of Molecular Sciences 22 (2021): 3962.

[253] E. N. Arwert, A. S. Harney, D. Entenberg, et al., “A Unidirectional Transition From Migratory to Perivascular Macrophage Is Required for Tumor Cell Intravasation,” Cell Reports 23 (2018): 1239-1248.

[254] R. Qin, W. Ren, G. Ya, et al., “Role of Chemokines in the Crosstalk Between Tumor and Tumor-associated Macrophages,” Clinical and Experimental Medicine 23 (2023): 1359-1373.

[255] D. K. Ahirwar, M. W. Nasser, M. M. Ouseph, et al., “Fibroblast-derived CXCL12 Promotes Breast Cancer Metastasis by Facilitating Tumor Cell Intravasation,” Oncogene 37 (2018): 4428-4442.

[256] Y. Yang, J. Li, W. Lei, et al., “CXCL12-CXCR4/CXCR7 Axis in Cancer: From Mechanisms to Clinical Applications,” International Journal of Biological Sciences 19 (2023): 3341-3359.

[257] K. Mortezaee, “CXCL12/CXCR4 axis in the Microenvironment of Solid Tumors: A Critical Mediator of Metastasis,” Life Sciences 249 (2020): 117534.

[258] D. P. Anastasiadou, A. Quesnel, C. L. Duran, P. S. Filippou, G. S. Karagiannis, “An Emerging Paradigm of CXCL12 Involvement in the Metastatic Cascade,” Cytokine & Growth Factor Reviews 75 (2024): 12-30.

[259] M. Cadamuro, S. Brivio, J. Mertens, et al., “Platelet-derived Growth Factor-D Enables Liver Myofibroblasts to Promote Tumor Lymphangiogenesis in Cholangiocarcinoma,” Journal of Hepatology 70 (2019): 700-709.

[260] J. Yan, G. Xiao, C. Yang, et al., “Cancer-Associated Fibroblasts Promote Lymphatic Metastasis in Cholangiocarcinoma via the PDGF-BB/PDGFR-β Mediated Paracrine Signaling Network,” Aging and Disease 15 (2024): 369-389.

[261] S. I. Ilyas, J. C. Mertens, S. F. Bronk, et al., “Platelet-derived Growth Factor Primes Cancer-associated Fibroblasts for Apoptosis,” Journal of Biological Chemistry 289 (2014): 22835-22849.

[262] M. Cadamuro, G. Nardo, S. Indraccolo, et al., “Platelet-derived Growth Factor-D and Rho GTPases Regulate Recruitment of Cancer-associated Fibroblasts in Cholangiocarcinoma,” Hepatology 58 (2013): 1042-1053.

[263] F. Orso, F. Virga, D. Dettori, et al., “Stroma-derived miR-214 Coordinates Tumor Dissemination,” Journal of Experimental & Clinical Cancer Research 42 (2023): 20.

[264] Y. Li, Y. Zheng, X. Tan, Y. Du, Y. Wei, S. Liu, “Extracellular Vesicle-mediated Pre-metastatic Niche Formation via Altering Host Microenvironments,” Frontiers in Immunology 15 (2024): 1367373.

[265] C. Jiang, Y. Li, Y. Li, et al., “Fibrinogen Promotes Gallbladder Cancer Cell Metastasis and Extravasation by Inducing ICAM1 Expression,” Medical Oncology 40 (2022): 10.

[266] C. Huang, Na Li, Z. Li, et al., “Tumour-derived Interleukin 35 Promotes Pancreatic Ductal Adenocarcinoma Cell Extravasation and Metastasis by Inducing ICAM1 Expression,” Nature Communications 8 (2017): 14035.

[267] S. Rana, K. Malinowska, M. Zöller, “Exosomal Tumor microRNA Modulates Premetastatic Organ Cells,” Neoplasia 15 (2013): 281-295.

[268] Q. Ji, L. Zhou, H. Sui, et al., “Primary Tumors Release ITGBL1-rich Extracellular Vesicles to Promote Distal Metastatic Tumor Growth Through Fibroblast-niche Formation,” Nature Communications 11 (2020): 1211.

[269] T. Fang, H. Lv, G. Lv, et al., “Tumor-derived Exosomal miR-1247-3p Induces Cancer-associated Fibroblast Activation to Foster Lung Metastasis of Liver Cancer,” Nature Communications 9 (2018): 191.

[270] T. Gener Lahav, O. Adler, Y. Zait, et al., “Melanoma-derived Extracellular Vesicles Instigate Proinflammatory Signaling in the Metastatic Microenvironment,” International Journal of Cancer 145 (2019): 2521-2534.

[271] K. Shahriari, F. Shen, A. Worrede-Mahdi, et al., “Cooperation Among Heterogeneous Prostate Cancer Cells in the Bone Metastatic Niche,” Oncogene 36 (2017): 2846-2856.

[272] P. Sandoval, J. A. Jiménez-Heffernan, Á. Rynne-Vidal, et al., “Carcinoma-associated Fibroblasts Derive From Mesothelial Cells via Mesothelial-to-mesenchymal Transition in Peritoneal Metastasis,” Journal of Pathology 231 (2013): 517-531.

[273] A. Rynne-Vidal, C. L. Au-Yeung, J. A. Jiménez-Heffernan, et al., “Mesothelial-to-mesenchymal Transition as a Possible Therapeutic Target in Peritoneal Metastasis of Ovarian Cancer,” Journal of Pathology 242 (2017): 140-151.

[274] J. E. Park, M. C. Lenter, R. N. Zimmermann, P. Garin-Chesa, L. J. Old, W. J. Rettig, “Fibroblast Activation Protein, a Dual Specificity Serine Protease Expressed in Reactive human Tumor Stromal Fibroblasts,” Journal of Biological Chemistry 274 (1999): 36505-36512.

[275] W. J. Rettig, et al., “Differential Expression of Cell Surface Antigens and Glial Fibrillary Acidic Protein in human Astrocytoma Subsets,” Cancer Research 46 (1986): 6406-6412.

[276] E. Puré, R. Blomberg, “Pro-tumorigenic Roles of Fibroblast Activation Protein in Cancer: Back to the Basics,” Oncogene 37 (2018): 4343-4357.

[277] T. Lindner, F. L. Giesel, C. Kratochwil, S. E. Serfling, “Radioligands Targeting Fibroblast Activation Protein (FAP),” Cancers (Basel) 13 (2021): 5744.

[278] W. J. Rettig, P. Garin-Chesa, J. H. Healey, S. L. Su, E. A. Jaffe, L. J. Old, “Identification of Endosialin, a Cell Surface Glycoprotein of Vascular Endothelial Cells in human Cancer,” PNAS 89 (1992): 10832-10836.

[279] T. Lindner, A. Loktev, A. Altmann, et al., “Development of Quinoline-Based Theranostic Ligands for the Targeting of Fibroblast Activation Protein,” Journal of Nuclear Medicine 59 (2018): 1415-1422.

[280] S. Basu, T. C. Kwee, S. Surti, E. A. Akin, D. Yoo, A. Alavi, “Fundamentals of PET and PET/CT Imaging,” Annals of the New York Academy of Sciences 1228 (2011): 1-18.

[281] Y. Gao, C. Wu, X. Chen, et al., “PET/CT Molecular Imaging in the Era of Immune-checkpoint Inhibitors Therapy,” Frontiers in Immunology 13 (2022): 1049043.

[282] J. Zang, R. Lin, X. Wen, et al., “A Head-to-Head Comparison of 68Ga-LNC1007 and 2-18F-FDG/68Ga-FAPI-02 PET/CT in Patients with Various Cancers,” Clinical Nuclear Medicine 48 (2023): 861-868.

[283] S. Zheng, J. Lin, Y. Zhu, et al., “68Ga-FAPI versus 18F-FDG PET/CT in Evaluating Newly Diagnosed Breast Cancer Patients: A Head-to-Head Comparative Study,” Clinical Nuclear Medicine 48 (2023): e104-e109.

[284] Y. Mori, K. Dendl, J. Cardinale, C. Kratochwil, F. L. Giesel, U. Haberkorn, “FAPI PET: Fibroblast Activation Protein Inhibitor Use in Oncologic and Nononcologic Disease,” Radiology 306 (2023): e220749.

[285] J. Millul, G. Bassi, J. Mock, et al., “An Ultra-high-affinity Small Organic Ligand of Fibroblast Activation Protein for Tumor-targeting Applications,” PNAS 118 (2021): e2101852118.

[286] P. Backhaus, F. Gierse, M. C. Burg, et al., “Translational Imaging of the Fibroblast Activation Protein (FAP) Using the New Ligand [(68)Ga]Ga-OncoFAP-DOTAGA,” European Journal of Nuclear Medicine and Molecular Imaging 49 (2022): 1822-1832.

[287] A. Galbiati, M. Bocci, D. Ravazza, et al., “Preclinical Evaluation of (177)Lu-OncoFAP-23, a Multivalent FAP-Targeted Radiopharmaceutical Therapeutic for Solid Tumors,” Journal of Nuclear Medicine 65 (2024): 1604-1610.

[288] A. Galbiati, P. Dorten, E. Gilardoni, et al., “Tumor-Targeted Interleukin 2 Boosts the Anticancer Activity of FAP-Directed Radioligand Therapeutics,” Journal of Nuclear Medicine 64 (2023): 1934-1940.

[289] D. Ventura, I. Ernst, B. Timma, M. Schäfers, P. Backhaus, “Basal Cell Carcinoma of the Head with Intense [ 68 Ga]OncoFAP Uptake,” Clinical Nuclear Medicine 50 (2025): e182-e183.

[290] D. Ventura, M. Schäfers, A. Yilmaz, L. Eckardt, D. Korthals, “Intense 68 Ga-OncoFAP Uptake as a New Promising Diagnostic Biomarker in Cardiac Sarcoidosis,” Clinical Nuclear Medicine 49 (2024): e278-e280.

[291] E. Sahin, T. Kus, A. Aytekin, et al., “68Ga-FAPI PET/CT as an Alternative to18F-FDG PET/CT in the Imaging of Invasive Lobular Breast Carcinoma,” Journal of Nuclear Medicine 65 (2024): 512-519.

[292] H. Kömek, C. Can, Y. Güzel, et al., “(68)Ga-FAPI-04 PET/CT, a New Step in Breast Cancer Imaging: A Comparative Pilot Study With the (18)F-FDG PET/CT,” Annals of Nuclear Medicine 35 (2021): 744-752.

[293] U. Elboga, E. Sahin, T. Kus, et al., “Superiority of (68)Ga-FAPI PET/CT Scan in Detecting Additional Lesions Compared to (18)FDG PET/CT Scan in Breast Cancer,” Annals of Nuclear Medicine 35 (2021): 1321-1331.

[294] S. Ballal, M. P. Yadav, F. Roesch, et al., “Head-to-Head Comparison Between [68Ga]Ga-DOTA.SA.FAPi and [18F]F-FDG PET/CT Imaging in Patients With Breast Cancer,” Pharmaceuticals 16 (2023): 521.

[295] J. Mcgale, S. Khurana, H. Howell, et al., “FAP-Targeted SPECT/CT and PET/CT Imaging for Breast Cancer Patients,” Clinical Nuclear Medicine 50 (2025): e138-e145.

[296] L. Wang, G. Tang, K. Hu, et al., “Comparison of (68)Ga-FAPI and (18)F-FDG PET/CT in the Evaluation of Advanced Lung Cancer,” Radiology 303 (2022): 191-199.

[297] F. L. Giesel, C. Kratochwil, J. Schlittenhardt, et al., “Head-to-head Intra-individual Comparison of Biodistribution and Tumor Uptake of (68)Ga-FAPI and (18)F-FDG PET/CT in Cancer Patients,” European Journal of Nuclear Medicine and Molecular Imaging 48 (2021): 4377-4385.

[298] J. Wu, H. Deng, H. Zhong, et al., “Comparison of (68)Ga-FAPI and (18)F-FDG PET/CT in the Evaluation of Patients with Newly Diagnosed Non-Small Cell Lung Cancer,” Frontiers in Oncology 12 (2022): 924223.

[299] R. Lin, Z. Lin, Z. Chen, et al., “[68Ga]Ga-DOTA-FAPI-04 PET/CT in the Evaluation of Gastric Cancer: Comparison With [18F]FDG PET/CT,” European Journal of Nuclear Medicine and Molecular Imaging 49 (2022): 2960-2971.

[300] H. Chen, Y. Pang, J. Wu, et al., “Comparison of [68Ga]Ga-DOTA-FAPI-04 and [18F] FDG PET/CT for the Diagnosis of Primary and Metastatic Lesions in Patients With Various Types of Cancer,” European Journal of Nuclear Medicine and Molecular Imaging 47 (2020): 1820-1832.

[301] J. Kuten, C. Levine, O. Shamni, et al., “Head-to-head Comparison of [(68)Ga]Ga-FAPI-04 and [(18)F]-FDG PET/CT in Evaluating the Extent of Disease in Gastric Adenocarcinoma,” European Journal of Nuclear Medicine and Molecular Imaging 49 (2022): 743-750.

[302] C. Gündoğan, H. Kömek, C. Can, et al., “Comparison of 18F-FDG PET/CT and 68Ga-FAPI-04 PET/CT in the Staging and Restaging of Gastric Adenocarcinoma,” Nuclear Medicine Communications 43 (2022): 64-72.

[303] B. Gu, Z. Yang, X. Du, et al., “Imaging of Tumor Stroma Using (68)Ga-FAPI PET/CT to Improve Diagnostic Accuracy of Primary Tumors in Head and Neck Cancer of Unknown Primary: A Comparative Imaging Trial,” Journal of Nuclear Medicine 65 (2024): 365-371.

[304] Y. Jiang, B. Wen, C. Li, et al., “The Performance of 68Ga-FAPI-04 PET/CT in Head and Neck Squamous Cell Carcinoma: A Prospective Comparison With 18F-FDG PET/CT,” European Journal of Nuclear Medicine and Molecular Imaging 50 (2023): 2114-2126.

[305] C. Qin, F. Liu, J. Huang, et al., “A Head-to-head Comparison of (68)Ga-DOTA-FAPI-04 and (18)F-FDG PET/MR in Patients With Nasopharyngeal Carcinoma: A Prospective Study,” European Journal of Nuclear Medicine and Molecular Imaging 48 (2021): 3228-3237.

[306] C. Promteangtrong, D. Siripongsatian, A. Jantarato, et al., “Head-to-Head Comparison of 68Ga-FAPI-46 and 18F-FDG PET/CT for Evaluation of Head and Neck Squamous Cell Carcinoma: A Single-Center Exploratory Study,” Journal of Nuclear Medicine 63 (2022): 1155-1161.

[307] X. Lin, Y. Li, S. Wang, et al., “Diagnostic Value of [(68)Ga]Ga-FAPI-04 in Patients With Colorectal Cancer in Comparison With [(18)F]F-FDG PET/CT,” Frontiers in Oncology 12 (2022): 1087792.

[308] Y. Pang, L. Zhao, Z. Luo, et al., “Comparison of 68Ga-FAPI and 18F-FDG Uptake in Gastric, Duodenal, and Colorectal Cancers,” Radiology 298 (2021): 393-402.

[309] H. Kömek, C. Can, I. Kaplan, et al., “Comparison of [(68) Ga]Ga-DOTA-FAPI-04 PET/CT and [(18)F]FDG PET/CT in Colorectal Cancer,” European Journal of Nuclear Medicine and Molecular Imaging 49 (2022): 3898-3909.

[310] Y. Dong, P. Sun, H. Wu, et al., “PET/CT Imaging Fibroblast Activation Protein in Initial Colorectal Cancer: Compared to 18F-FDG PET/CT,” Nuclear Medicine Communications 44 (2023): 1011-1019.

[311] B. Wang, X. Zhao, Y. Liu, et al., “Comparison of 68Ga-FAPI-04 PET/CT With 18F-FDG PET/CT for Diagnosis and Staging of Gastric and Colorectal Cancer,” Nuclear Medicine Communications 45 (2024): 612-621.

[312] L. Lan, S. Zhang, T. Xu, et al., “Prospective Comparison of 68Ga-FAPI versus 18F-FDG PET/CT for Tumor Staging in Biliary Tract Cancers,” Radiology 304 (2022): 648-657.

[313] Q. Shu, X. He, Xi Chen, M. Liu, Y. Chen, L. Cai, “Head-to-Head Comparison of 18F-FDG and 68Ga-FAPI-04 PET/CT for Radiological Evaluation of Cervical Cancer,” Clinical Nuclear Medicine 48 (2023): 928-932.

[314] V. Rajaraman, L. A. Meenakshi, A. J. Selvaraj, B. Pottakkat, D. Halanaik, “Role of 68 Ga-FAPI PET/CT in Assessing Hepatobiliary Malignancies : A Prospective Pilot Study,” Clinical Nuclear Medicine 48 (2023): e281-e288.

[315] Z. Cheng, S. Zou, S. Cheng, S. Song, X. Zhu, “Comparison of 18F-FDG, 68Ga-FAPI, and 68Ga-DOTATATE PET/CT in a Patient with Pancreatic Neuroendocrine Tumor,” Clinical Nuclear Medicine 46 (2021): 764-765.

[316] M. Röhrich, A. Loktev, A. K. Wefers, et al., “IDH-wildtype Glioblastomas and Grade III/IV IDH-mutant Gliomas Show Elevated Tracer Uptake in Fibroblast Activation Protein-specific PET/CT,” European Journal of Nuclear Medicine and Molecular Imaging 46 (2019): 2569-2580.

[317] P. Windisch, M. Röhrich, S. Regnery, et al., “Fibroblast Activation Protein (FAP) Specific PET for Advanced Target Volume Delineation in Glioblastoma,” Radiotherapy and Oncology 150 (2020): 159-163.

[318] J. Zang, X. Wen, R. Lin, et al., “Synthesis, Preclinical Evaluation and Radiation Dosimetry of a Dual Targeting PET Tracer [(68)Ga]Ga-FAPI-RGD,” Theranostics 12 (2022): 7180-7190.

[319] L. Feng, W. Hu, X. Zeng, et al., “Development and Evaluation of DOTA-FAPI-Maleimide as a Novel Radiotracer for Tumor Theranostic With Extended Circulation,” Molecular Pharmaceutics 21 (2024): 4386-4394.

[320] Y. Wei, L. Ma, P. Li, et al., “FAPI Compared With FDG PET/CT for Diagnosis of Primary and Metastatic Lung Cancer,” Radiology 308 (2023): e222785.

[321] C. Qin, F. Shao, Y. Gai, et al., “(68)Ga-DOTA-FAPI-04 PET/MR in the Evaluation of Gastric Carcinomas: Comparison With (18)F-FDG PET/CT,” Journal of Nuclear Medicine 63 (2022): 81-88.

[322] W.-T. Dou, H.-H. Han, A. C. Sedgwick, et al., “Fluorescent Probes for the Detection of Disease-associated Biomarkers,” Science Bulletin (Beijing) 67 (2022): 853-878.

[323] J. S. D. Mieog, F. B. Achterberg, A. Zlitni, et al., “Fundamentals and Developments in Fluorescence-guided Cancer Surgery,” Nature Reviews Clinical Oncology 19 (2022): 9-22.

[324] S. Su, W. J. Scott, M. S. Allen, et al., “Patterns of Survival and Recurrence After Surgical Treatment of Early Stage Non-small Cell Lung Carcinoma in the ACOSOG Z0030 (ALLIANCE) Trial,” Journal of Thoracic and Cardiovascular Surgery 147 (2014): 747-752. Discussion 752-743.

[325] H. Saji, M. Okada, M. Tsuboi, et al., “Segmentectomy versus Lobectomy in Small-sized Peripheral Non-small-cell Lung Cancer (JCOG0802/WJOG4607L): A Multicentre, Open-label, Phase 3, Randomised, Controlled, Non-inferiority Trial,” Lancet 399 (2022): 1607-1617.

[326] T. Fabian, A. S. Bryant, A. L. Mouhlas, J. A. Federico, R. J. Cerfolio, “Survival After Resection of Synchronous Non-small Cell Lung Cancer,” Journal of Thoracic and Cardiovascular Surgery 142 (2011): 547-553.

[327] J. D. Predina, A. D. Newton, C. Connolly, et al., “Identification of a Folate Receptor-Targeted Near-Infrared Molecular Contrast Agent to Localize Pulmonary Adenocarcinomas,” Molecular Therapy 26 (2018): 390-403.

[328] O. T. Okusanya, E. M. Dejesus, J. X. Jiang, et al., “Intraoperative Molecular Imaging Can Identify Lung Adenocarcinomas During Pulmonary Resection,” Journal of Thoracic and Cardiovascular Surgery 150 (2015): 28-35. e21.

[329] H. Li, D. Xia, L. Meng, et al., “FAP-targeted Delivery of Radioiodinated Probes: A Progressive Albumin-driven Strategy for Tumor Theranostics,” Journal of Controlled Release 382 (2025): 113678.

[330] X. Wen, P. Xu, M. Shi, et al., “Evans Blue-modified Radiolabeled Fibroblast Activation Protein Inhibitor as Long-acting Cancer Therapeutics,” Theranostics 12 (2022): 422-433.

[331] H. Fu, J. Huang, T. Zhao, et al., “Fibroblast Activation Protein-Targeted Radioligand Therapy With 177Lu-EB-FAPI for Metastatic Radioiodine-Refractory Thyroid Cancer: First-in-Human, Dose-Escalation Study,” Clinical Cancer Research 29 (2023): 4740-4750.

[332] D. N. Dorst, M. Rijpkema, M. Buitinga, et al., “Targeting of Fibroblast Activation Protein in Rheumatoid Arthritis Patients: Imaging and Ex Vivo Photodynamic Therapy,” Rheumatology 61 (2022): 2999-3009.

[333] S. Y. Liu, H. Wang, G. Nie, “Ultrasensitive Fibroblast Activation Protein-α-Activated Fluorogenic Probe Enables Selective Imaging and Killing of Melanoma in Vivo,” ACS Sens 7 (2022): 1837-1846.

[334] F. L. Tansi, R. Rüger, C. Böhm, et al., “Potential of Activatable FAP-targeting Immunoliposomes in Intraoperative Imaging of Spontaneous Metastases,” Biomaterials 88 (2016): 70-82.

[335] X. Zhao, G. Zhang, J. Chen, et al., “A Rationally Designed Nuclei-targeting FAPI 04-based Molecular Probe With Enhanced Tumor Uptake for PET/CT and Fluorescence Imaging,” European Journal of Nuclear Medicine and Molecular Imaging 51 (2024): 1593-1604.

[336] W. K. Tsai, K. A. Zettlitz, R. Tavaré, N. Kobayashi, R. E. Reiter, A. M. Wu, “Dual-Modality ImmunoPET/Fluorescence Imaging of Prostate Cancer With an Anti-PSCA Cys-Minibody,” Theranostics 8 (2018): 5903-5914.

[337] S. Lütje, M. Rijpkema, W. Helfrich, W. J. Oyen, O. C. Boerman, “Targeted Radionuclide and Fluorescence Dual-modality Imaging of Cancer: Preclinical Advances and Clinical Translation,” Molecular Imaging and Biology 16 (2014): 747-755.

[338] H. Deng, Y. Bai, J. Xiang, et al., “Photoacoustic/Ultrasound Dual-modality Imaging for Marker Clip Localization in Neoadjuvant Chemotherapy of Breast Cancer,” Journal of Biomedial Optics 29 (2024): S11525.

[339] X. Chen, H. Zhou, X. Li, et al., “Plectin-1 Targeted Dual-modality Nanoparticles for Pancreatic Cancer Imaging,” EBioMedicine 30 (2018): 129-137.

[340] H. Wahyudi, A. A. Reynolds, Y. Li, S. C. Owen, S. M. Yu, “Targeting Collagen for Diagnostic Imaging and Therapeutic Delivery,” Journal of Controlled Release 240 (2016): 323-331.

[341] S. Chen, K. Li, X. Chen, S. Lei, J. Lin, P. Huang, “Reversibly Photoswitchable Protein Assemblies With Collagen Affinity for in Vivo Photoacoustic Imaging of Tumors,” Science Advances 10 (2024): eadn8274.

[342] E. Brown, T. Mckee, E. Ditomaso, et al., “Dynamic Imaging of Collagen and Its Modulation in Tumors in Vivo Using Second-harmonic Generation,” Nature Medicine 9 (2003): 796-800.

[343] W. Adi, B. E. Rubio Perez, Y. Liu, S. Runkle, K. W. Eliceiri, F. Yesilkoy, “Machine Learning-assisted Mid-infrared Spectrochemical Fibrillar Collagen Imaging in Clinical Tissues,” Journal of Biomedial Optics 29 (2024): 093511.

[344] T. Ottens, S. Barbieri, M. R. Orton, et al., “Deep Learning DCE-MRI Parameter Estimation: Application in Pancreatic Cancer,” Medical Image Analysis 80 (2022): 102512.

[345] C. Militello, L. Rundo, M. Dimarco, et al., “3D DCE-MRI Radiomic Analysis for Malignant Lesion Prediction in Breast Cancer Patients,” Academic Radiology 29 (2022): 830-840.

[346] Q. Ma, X. Lu, Q. Chen, H. Gong, J. Lei, “Multiphases DCE-MRI Radiomics Nomogram for Preoperative Prediction of Lymphovascular Invasion in Invasive Breast Cancer,” Academic Radiology 31 (2024): 4743-4758.

[347] T. Lv, Y. Wu, Y. Wang, et al., “A Hybrid Hemodynamic Knowledge-powered and Feature Reconstruction-guided Scheme for Breast Cancer Segmentation Based on DCE-MRI,” Medical Image Analysis 82 (2022): 102572.

[348] A. Gubern-Mérida, R. Martí, J. Melendez, et al., “Automated Localization of Breast Cancer in DCE-MRI,” Medical Image Analysis 20 (2015): 265-274.

[349] M. Polasek, Y. Yang, D. T. Schühle, et al., “Molecular MR Imaging of Fibrosis in a Mouse Model of Pancreatic Cancer,” Scientific Reports 7 (2017): 8114.

[350] P. Farace, F. Merigo, S. Fiorini, et al., “DCE-MRI Using Small-molecular and Albumin-binding Contrast Agents in Experimental Carcinomas With Different Stromal Content,” European Journal of Radiology 78 (2011): 52-59.

[351] N. Talebloo, M. A. O. Bernal, E. Kenyon, C. L. Mallett, A. Fazleabas, A. Moore, “Detection of Endometriosis Lesions Using Gd-Based Collagen I Targeting Probe in Murine Models of Endometriosis,” Molecular Imaging and Biology 25 (2023): 833-843.

[352] W. D. Travis, S. Dacic, I. Wistuba, et al., “IASLC Multidisciplinary Recommendations for Pathologic Assessment of Lung Cancer Resection Specimens after Neoadjuvant Therapy,” Journal of Thoracic Oncology 15 (2020): 709-740.

[353] C. Cao, A. Guo, C. Chen, et al., “Systematic Review of Neoadjuvant Immunotherapy for Patients with Non-Small Cell Lung Cancer,” Seminars in Thoracic and Cardiovascular Surgery 33 (2021): 850-857.

[354] D. J. Erstad, M. Sojoodi, M. S. Taylor, et al., “Fibrotic Response to Neoadjuvant Therapy Predicts Survival in Pancreatic Cancer and Is Measurable With Collagen-Targeted Molecular MRI,” Clinical Cancer Research 26 (2020): 5007-5018.

[355] D. Izquierdo-Garcia, P. Désogère, M. L. Fur, et al., “Biodistribution, Dosimetry, and Pharmacokinetics of (68)Ga-CBP8: A Type I Collagen-Targeted PET Probe,” Journal of Nuclear Medicine 64 (2023): 775-781.

[356] S. A. Esfahani, H. Ma, S. Krishna, et al., “Collagen Type I PET/MRI Enables Evaluation of Treatment Response in Pancreatic Cancer in Pre-clinical and First-in-human Translational Studies,” Theranostics 14 (2024): 5745-5761.

[357] P. Désogère, L. F. Tapias, L. P. Hariri, et al., “Type I Collagen-targeted PET Probe for Pulmonary Fibrosis Detection and Staging in Preclinical Models,” Science Translational Medicine 9 (2017): eaaf4696.

[358] J. Xiong, L. Yan, C. Zou, et al., “Integrins Regulate Stemness in Solid Tumor: An Emerging Therapeutic Target,” Journal of Hematology & Oncology 14 (2021): 177.

[359] F. Liu, Q. Wu, Z. Dong, K. Liu, “Integrins in Cancer: Emerging Mechanisms and Therapeutic Opportunities,” Pharmacology & Therapeutics 247 (2023): 108458.

[360] H. Hamidi, J. Ivaska, “Every Step of the Way: Integrins in Cancer Progression and Metastasis,” Nature Reviews Cancer 18 (2018): 533-548.

[361] J. S. Desgrosellier, D. A. Cheresh, “Integrins in Cancer: Biological Implications and Therapeutic Opportunities,” Nature Reviews Cancer 10 (2010): 9-22.

[362] R. J. Slack, S. J. F. Macdonald, J. A. Roper, R. G. Jenkins, R. J. D. Hatley, “Emerging Therapeutic Opportunities for Integrin Inhibitors,” Nature Reviews Drug Discovery 21 (2022): 60-78.

[363] L. Koivisto, J. Bi, L. Häkkinen, H. Larjava, “Integrin αvβ6: Structure, Function and Role in Health and Disease,” International Journal of Biochemistry & Cell Biology 99 (2018): 186-196.

[364] R. H. Kimura, L. Wang, B. Shen, et al., “Evaluation of Integrin Αvβ(6) Cystine Knot PET Tracers to Detect Cancer and Idiopathic Pulmonary Fibrosis,” Nature Communications 10 (2019): 4673.

[365] E. Sahai, I. Astsaturov, E. Cukierman, et al., “A Framework for Advancing Our Understanding of Cancer-associated Fibroblasts,” Nature Reviews Cancer 20 (2020): 174-186.

[366] X. Chen, E. Song, “Turning Foes to Friends: Targeting Cancer-associated Fibroblasts,” Nat Rev Drug Discovery 18 (2019): 99-115.

[367] K. C. Valkenburg, A. E. de Groot, K. J. Pienta, “Targeting the Tumour Stroma to Improve Cancer Therapy,” Nature reviews Clinical oncology 15 (2018): 366-381.

[368] C. Berking, et al., “Transforming Growth Factor-beta1 Increases Survival of human Melanoma Through Stroma Remodeling,” Cancer Research 61 (2001): 8306-8316.

[369] J. A. Tuxhorn, S. J. McAlhany, F. Yang, T. D. Dang, D. R. Rowley, “Inhibition of Transforming Growth Factor-beta Activity Decreases Angiogenesis in a human Prostate Cancer-reactive Stroma Xenograft Model,” Cancer Research 62 (2002): 6021-6025.

[370] N. Cheng, A. Chytil, Y. Shyr, A. Joly, H. L. Moses, “Enhanced Hepatocyte Growth Factor Signaling by Type II Transforming Growth Factor-beta Receptor Knockout Fibroblasts Promotes Mammary Tumorigenesis,” Cancer Research 67 (2007): 4869-4877.

[371] S. Mariathasan, S. J. Turley, D. Nickles, et al., “TGFβ Attenuates Tumour Response to PD-L1 Blockade by Contributing to Exclusion of T Cells,” Nature 554 (2018): 544-548.

[372] D. V. F. Tauriello, S. Palomo-Ponce, D. Stork, et al., “TGFβ Drives Immune Evasion in Genetically Reconstituted Colon Cancer Metastasis,” Nature 554 (2018): 538-543.

[373] I. Belhabib, S. Zaghdoudi, C. Lac, C. Bousquet, C. Jean, “Extracellular Matrices and Cancer-Associated Fibroblasts: Targets for Cancer Diagnosis and Therapy?,” Cancers (Basel) 13 (2021): 3466.

[374] T. Yamazaki, A. J. Gunderson, M. Gilchrist, et al., “Galunisertib plus Neoadjuvant Chemoradiotherapy in Patients With Locally Advanced Rectal Cancer: A Single-arm, Phase 2 Trial,” The Lancet Oncology 23 (2022): 1189-1200.

[375] A. Wick, A. Desjardins, C. Suarez, et al., “Phase 1b/2a Study of galunisertib, a Small Molecule Inhibitor of Transforming Growth Factor-beta Receptor I, in Combination With Standard Temozolomide-based Radiochemotherapy in Patients With Newly Diagnosed Malignant Glioma,” Investigational New Drugs 38 (2020): 1570-1579.

[376] J. Rodon, M. A. Carducci, J. M. Sepulveda-Sánchez, et al., “First-in-human Dose Study of the Novel Transforming Growth Factor-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Patients With Advanced Cancer and Glioma,” Clinical Cancer Research 21 (2015): 553-560.

[377] J. Rodón, M. Carducci, J. M. Sepulveda-Sánchez, et al., “Pharmacokinetic, Pharmacodynamic and Biomarker Evaluation of Transforming Growth Factor-β Receptor I Kinase Inhibitor, galunisertib, in Phase 1 Study in Patients With Advanced Cancer,” Investigational New Drugs 33 (2015): 357-370.

[378] E. Nadal, M. Saleh, S. P. Aix, et al., “A Phase Ib/II Study of galunisertib in Combination With nivolumab in Solid Tumors and Non-small Cell Lung Cancer,” BMC Cancer 23 (2023): 708.

[379] D. Melisi, D.-Y. Oh, A. Hollebecque, et al., “Safety and Activity of the TGFβ Receptor I Kinase Inhibitor galunisertib plus the Anti-PD-L1 Antibody Durvalumab in Metastatic Pancreatic Cancer,” Journal for ImmunoTherapy of Cancer 9 (2021): e002068.

[380] D. Melisi, R. Garcia-Carbonero, T. Macarulla, et al., “Galunisertib plus Gemcitabine vs. gemcitabine for First-line Treatment of Patients With Unresectable Pancreatic Cancer,” British Journal of Cancer 119 (2018): 1208-1214.

[381] R. K. Kelley, E. Gane, E. Assenat, et al., “A Phase 2 Study of Galunisertib (TGF-β1 Receptor Type I Inhibitor) and Sorafenib in Patients with Advanced Hepatocellular Carcinoma,” Clinical and Translational Gastroenterology 10 (2019): e00056.

[382] M. Ikeda, H. Takahashi, S. Kondo, et al., “Phase 1b Study of galunisertib in Combination With Gemcitabine in Japanese Patients With Metastatic or Locally Advanced Pancreatic Cancer,” Cancer Chemotheraphy and Pharmacology 79 (2017): 1169-1177.

[383] M. Ikeda, M. Morimoto, M. Tajimi, et al., “A Phase 1b Study of Transforming Growth Factor-beta Receptor I Inhibitor galunisertib in Combination With sorafenib in Japanese Patients With Unresectable Hepatocellular Carcinoma,” Investigational New Drugs 37 (2019): 118-126.

[384] J. J. Harding, R. K. Do, A. Yaqubie, et al., “Phase 1b Study of Galunisertib and Ramucirumab in Patients With Advanced Hepatocellular Carcinoma,” Cancer Medicine 10 (2021): 3059-3067.

[385] Y. Fujiwara, H. Nokihara, Y. Yamada, et al., “Phase 1 Study of galunisertib, a TGF-beta Receptor I Kinase Inhibitor, in Japanese Patients With Advanced Solid Tumors,” Cancer Chemotheraphy and Pharmacology 76 (2015): 1143-1152.

[386] S. Faivre, A. Santoro, R. K. Kelley, et al., “Novel Transforming Growth Factor Beta Receptor I Kinase Inhibitor Galunisertib (LY2157299) in Advanced Hepatocellular Carcinoma,” Liver International 39 (2019): 1468-1477.

[387] E. G. Chiorean, V. Picozzi, C.-P. Li, et al., “Efficacy and Safety of abemaciclib Alone and With PI3K/mTOR Inhibitor LY3023414 or Galunisertib versus Chemotherapy in Previously Treated Metastatic Pancreatic Adenocarcinoma: A Randomized Controlled Trial,” Cancer Medicine 12 (2023): 20353-20364.

[388] A. A. Brandes, A. F. Carpentier, S. Kesari, et al., “A Phase II Randomized Study of galunisertib Monotherapy or Galunisertib plus Lomustine Compared With Lomustine Monotherapy in Patients With Recurrent Glioblastoma,” Neuro-Oncology 18 (2016): 1146-1156.

[389] S. Pietrobono, F. Sabbadini, M. Bertolini, et al., “Autotaxin Secretion Is a Stromal Mechanism of Adaptive Resistance to TGFβ Inhibition in Pancreatic Ductal Adenocarcinoma,” Cancer Research 84 (2024): 118-132.

[390] T. A. Yap, M. Vieito, C. Baldini, et al., “First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients With Advanced Cancer,” Clinical Cancer Research 27 (2021): 6666-6676.

[391] Z. Li, W. Xu, J. Yang, et al., “A Tumor Microenvironments-Adapted Polypeptide Hydrogel/Nanogel Composite Boosts Antitumor Molecularly Targeted Inhibition and Immunoactivation,” Advanced Materials 34 (2022): e2200449.

[392] P. Zhang, C. Qin, N. Liu, et al., “The Programmed Site-specific Delivery of LY3200882 and PD-L1 siRNA Boosts Immunotherapy for Triple-negative Breast Cancer by Remodeling Tumor Microenvironment,” Biomaterials 284 (2022): 121518.

[393] P. Hamon, M. Gerbé De Thoré, M. Classe, et al., “TGFβ Receptor Inhibition Unleashes Interferon-β Production by Tumor-associated Macrophages and Enhances Radiotherapy Efficacy,” Journal for ImmunoTherapy of Cancer 10 (2022): e003519.

[394] E. Malek, P. S. Rana, M. Swamydas, et al., “The TGFβ Type I Receptor Kinase Inhibitor vactosertib in Combination With pomalidomide in Relapsed/Refractory Multiple Myeloma: A Phase 1b Trial,” Nature Communications 15 (2024): 7388.

[395] S. Y. Jung, S. Hwang, J. M. Clarke, et al., “Pharmacokinetic Characteristics of vactosertib, a New Activin Receptor-Like Kinase 5 Inhibitor, in Patients With Advanced Solid Tumors in a First-in-human Phase 1 Study,” Investigational New Drugs 38 (2020): 812-820.

[396] J.-H. Ahn, J. Lee, C. Park, et al., “Clinical Activity of TGF-β Inhibitor Vactosertib in Combination With Imatinib in Desmoid Tumors: A Multicenter Phase Ib/II Study,” Clinical Cancer Research 30 (2024): 1457-1465.

[397] C. Feig, J. O. Jones, M. Kraman, et al., “Targeting CXCL12 From FAP-expressing Carcinoma-associated Fibroblasts Synergizes With Anti-PD-L1 Immunotherapy in Pancreatic Cancer,” PNAS 110 (2013): 20212-20217.

[398] D. Zboralski, K. Hoehlig, D. Eulberg, A. Frömming, A. Vater, “Increasing Tumor-Infiltrating T Cells Through Inhibition of CXCL12 With NOX-A12 Synergizes With PD-1 Blockade,” Cancer Immunology Research 5 (2017): 950-956.

[399] J. B. Candido, J. P. Morton, P. Bailey, et al., “CSF1R(+) Macrophages Sustain Pancreatic Tumor Growth Through T Cell Suppression and Maintenance of Key Gene Programs That Define the Squamous Subtype,” Cell Reports 23 (2018): 1448-1460.

[400] Y. Zhu, B. L. Knolhoff, M. A. Meyer, et al., “CSF1/CSF1R blockade Reprograms Tumor-infiltrating Macrophages and Improves Response to T-cell Checkpoint Immunotherapy in Pancreatic Cancer Models,” Cancer Research 74 (2014): 5057-5069.

[401] J. Yang, A. Kumar, A. E. Vilgelm, et al., “Loss of CXCR4 in Myeloid Cells Enhances Antitumor Immunity and Reduces Melanoma Growth Through NK Cell and FASL Mechanisms,” Cancer Immunology Research 6 (2018): 1186-1198.

[402] B. Bockorny, V. Semenisty, T. Macarulla, et al., “BL-8040, a CXCR4 Antagonist, in Combination With pembrolizumab and Chemotherapy for Pancreatic Cancer: The COMBAT Trial,” Nature Medicine 26 (2020): 878-885.

[403] M. Abraham, Y. Pereg, B. Bulvik, et al., “Single Dose of the CXCR4 Antagonist BL-8040 Induces Rapid Mobilization for the Collection of Human CD34(+) Cells in Healthy Volunteers,” Clinical Cancer Research 23 (2017): 6790-6801.

[404] P. M. Voorhees, J. L. Kaufman, J. Laubach, et al., “Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone for Transplant-eligible Newly Diagnosed Multiple Myeloma: The GRIFFIN Trial,” Blood 136 (2020): 936-945.

[405] G. L. Uy, M. P. Rettig, R. M. Stone, et al., “A Phase 1/2 Study of Chemosensitization With plerixafor plus G-CSF in Relapsed or Refractory Acute Myeloid Leukemia,” Blood Cancer Journal 7 (2017): e542.

[406] S. Sidana, A. K. Bankova, H. Hosoya, et al., “Phase II Study of Novel CXCR2 Agonist and Plerixafor for Rapid Stem Cell Mobilization in Patients With Multiple Myeloma,” Blood Cancer Journal 14 (2024): 173.

[407] B. Morland, T. Kepak, S. Dallorso, et al., “Plerixafor Combined With Standard Regimens for Hematopoietic Stem Cell Mobilization in Pediatric Patients With Solid Tumors Eligible for Autologous Transplants: Two-arm Phase I/II Study (MOZAIC),” Bone Marrow Transplantation 55 (2020): 1744-1753.

[408] D. H. Mcdermott, D. Velez, E. Cho, et al., “A Phase III Randomized Crossover Trial of plerixafor versus G-CSF for Treatment of WHIM Syndrome,” Journal of Clinical Investigation 133 (2023): e164918.

[409] S. M. Devine, R. Vij, M. Rettig, et al., “Rapid Mobilization of Functional Donor Hematopoietic Cells Without G-CSF Using AMD3100, an Antagonist of the CXCR4/SDF-1 Interaction,” Blood 112 (2008): 990-998.

[410] S. M. Devine, N. Flomenberg, D. H. Vesole, et al., “Rapid Mobilization of CD34+ Cells Following Administration of the CXCR4 Antagonist AMD3100 to Patients With Multiple Myeloma and non-Hodgkin's Lymphoma,” Journal of Clinical Oncology 22 (2004): 1095-1102.

[411] S. A. Patel, M. B. Nilsson, Y. Yang, et al., “IL6 Mediates Suppression of T- and NK-cell Function in EMT-associated TKI-resistant EGFR-mutant NSCLC,” Clinical Cancer Research 29 (2023): 1292-1304.

[412] T. A. Mace, R. Shakya, J. R. Pitarresi, et al., “IL-6 and PD-L1 Antibody Blockade Combination Therapy Reduces Tumour Progression in Murine Models of Pancreatic Cancer,” Gut 67 (2018): 320-332.

[413] Z. Guo, H. Zhang, Y. Fu, et al., “Cancer-associated Fibroblasts Induce Growth and Radioresistance of Breast Cancer Cells Through Paracrine IL-6,” Cell Death Discov 9 (2023): 6.

[414] A. Dittmer, J. Dittmer, “A CAF-Fueled TIMP-1/CD63/ITGB1/STAT3 Feedback Loop Promotes Migration and Growth of Breast Cancer Cells,” Cancers (Basel) 14 (2022): 4983.

[415] A. M. Skoda, D. Simovic, V. Karin, V. Kardum, S. Vranic, L. Serman, “The Role of the Hedgehog Signaling Pathway in Cancer: A Comprehensive Review,” Bosnian Journal of Basic Medical Sciences 18 (2018): 8-20.

[416] A. Giammona, E. Crivaro, B. Stecca, “Emerging Roles of Hedgehog Signaling in Cancer Immunity,” International Journal of Molecular Sciences 24 (2023): 1321.

[417] N. Geyer, M. Gerling, “Hedgehog Signaling in Colorectal Cancer: All in the Stroma?,” International Journal of Molecular Sciences 22 (2021): 1025.

[418] G. J. Yoshida, “Regulation of Heterogeneous Cancer-associated Fibroblasts: The Molecular Pathology of Activated Signaling Pathways,” Journal of Experimental & Clinical Cancer Research 39 (2020): 112.

[419] T. Østerlund, P. Kogerman, “Hedgehog Signalling: How to Get From Smo to Ci and Gli,” Trends in Cell Biology 16 (2006): 176-180.

[420] J. Jiang, “Hedgehog Signaling Mechanism and Role in Cancer,” Seminars in Cancer Biology 85 (2022): 107-122.

[421] A. Sekulic, M. R. Migden, A. E. Oro, et al., “Efficacy and Safety of vismodegib in Advanced Basal-cell Carcinoma,” New England Journal of Medicine 366 (2012): 2171-2179.

[422] V. Ruiz-Salas, M. Alegre, A. López-Ferrer, J. R. Garcés, “Vismodegib: A Review,” Actas Dermo-Sifiliograficas 105 (2014): 744-751.

[423] J. E. Frampton, N. Basset-Séguin, “Vismodegib: A Review in Advanced Basal Cell Carcinoma,” Drugs 78 (2018): 1145-1156.

[424] R. Dummer, P. A. Ascierto, N. Basset-Seguin, et al., “Sonidegib and vismodegib in the Treatment of Patients With Locally Advanced Basal Cell Carcinoma: A Joint Expert Opinion,” Journal of the European Academy of Dermatology and Venereology 34 (2020): 1944-1956.

[425] B. Stecca, C. Mas, A. R. I. Altaba, “Interference With HH-GLI Signaling Inhibits Prostate Cancer,” Trends in Molecular Medicine 11 (2005): 199-203.

[426] A. N. Sigafoos, B. D. Paradise, M. E. Fernandez-Zapico, “Hedgehog/GLI Signaling Pathway: Transduction, Regulation, and Implications for Disease,” Cancers (Basel) 13 (2021): 3410.

[427] P. Zhu, Li Wang, P. Xu, et al., “GANT61 elevates Chemosensitivity to Cisplatin Through Regulating the Hedgehog, AMPK and cAMP Pathways in Ovarian Cancer,” Future Medicinal Chemistry 14 (2022): 479-500.

[428] K. Q. Zhang, X. D. Chu, “GANT61 plays Antitumor Effects by Inducing Oxidative Stress Through the miRNA-1286/RAB31 Axis in Osteosarcoma,” Cell Biology International 45 (2021): 61-73.

[429] A. H. M. El-Kishky, N. Moussa, M. W. Helmy, M. Haroun, “GANT61/BI-847325 Combination: A New Hope in Lung Cancer Treatment,” Medical Oncology 39 (2022): 144.

[430] Y. Jiang, T. L. Benz, S. B. Long, “Substrate and Product Complexes Reveal Mechanisms of Hedgehog Acylation by HHAT,” Science 372 (2021): 1215-1219.

[431] J. A. Buglino, M. D. Resh, “Hhat Is a Palmitoylacyltransferase With Specificity for N-palmitoylation of Sonic Hedgehog,” Journal of Biological Chemistry 283 (2008): 22076-22088.

[432] G. Xu, B. An, R. Wang, et al., “RBM10 deficiency Promotes Brain Metastasis by Modulating Sphingolipid Metabolism in a BBB Model of EGFR Mutant Lung Adenocarcinoma,” Journal of Experimental & Clinical Cancer Research 44 (2025): 95.

[433] E. Petrova, A. Matevossian, M. D. Resh, “Hedgehog Acyltransferase as a Target in Pancreatic Ductal Adenocarcinoma,” Oncogene 34 (2015): 263-268.

[434] A. Matevossian, M. D. Resh, “Hedgehog Acyltransferase as a Target in Estrogen Receptor Positive, HER2 Amplified, and Tamoxifen Resistant Breast Cancer Cells,” Molecular Cancer 14 (2015): 72.

[435] B. C. Özdemir, T. Pentcheva-Hoang, J. L. Carstens, et al., “Depletion of Carcinoma-associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer With Reduced Survival,” Cancer Cell 25 (2014): 719-734.

[436] A. D. Rhim, P. E. Oberstein, D. H. Thomas, et al., “Stromal Elements Act to Restrain, Rather Than Support, Pancreatic Ductal Adenocarcinoma,” Cancer Cell 25 (2014): 735-747.

[437] S. Shahvali, N. Rahiman, M. R. Jaafari, L. Arabi, “Targeting Fibroblast Activation Protein (FAP): Advances in CAR-T Cell, Antibody, and Vaccine in Cancer Immunotherapy,” Drug Delivery and Translational Research 13 (2023): 2041-2056.

[438] M. Nurmik, P. Ullmann, F. Rodriguez, S. Haan, E. Letellier, “In Search of Definitions: Cancer-associated Fibroblasts and Their Markers,” International Journal of Cancer 146 (2020): 895-905.

[439] E. J. Hamson, F. M. Keane, S. Tholen, O. Schilling, M. D. Gorrell, “Understanding Fibroblast Activation Protein (FAP): Substrates, Activities, Expression and Targeting for Cancer Therapy,” Proteomics Clinical Applications 8 (2014): 454-463.

[440] A. A. Fitzgerald, L. M. Weiner, “The Role of Fibroblast Activation Protein in Health and Malignancy,” Cancer and Metastasis Reviews 39 (2020): 783-803.

[441] S. Welt, C. R. Divgi, A. M. Scott, et al., “Antibody Targeting in Metastatic Colon Cancer: A Phase I Study of Monoclonal Antibody F19 Against a Cell-surface Protein of Reactive Tumor Stromal Fibroblasts,” Journal of Clinical Oncology 12 (1994): 1193-1203.

[442] R. D. Hofheinz, et al., “Stromal Antigen Targeting by a Humanised Monoclonal Antibody: An Early Phase II Trial of sibrotuzumab in Patients With Metastatic Colorectal Cancer,” Onkologie 26 (2003): 44-48.

[443] A. M. Scott, G. Wiseman, S. Welt, et al., “A Phase I Dose-escalation Study of sibrotuzumab in Patients With Advanced or Metastatic Fibroblast Activation Protein-positive Cancer,” Clinical Cancer Research 9 (2003): 1639-1647.

[444] J. Fang, L. Xiao, K.-I. Joo, et al., “A Potent Immunotoxin Targeting Fibroblast Activation Protein for Treatment of Breast Cancer in Mice,” International Journal of Cancer 138 (2016): 1013-1023.

[445] J. Fang, B. Hu, S. Li, C. Zhang, Y. Liu, P. Wang, “A Multi-antigen Vaccine in Combination With an Immunotoxin Targeting Tumor-associated Fibroblast for Treating Murine Melanoma,” Molecular Therapy Oncology 3 (2016): 16007.

[446] X.-Y. Cui, Z. Li, Z. Kong, et al., “Covalent Targeted Radioligands Potentiate Radionuclide Therapy,” Nature 630 (2024): 206-213.

[447] M. Xu, P,. Zhang, J. Ding, J. Chen, L. Huo, Z. Liu, “Albumin Binder-Conjugated Fibroblast Activation Protein Inhibitor Radiopharmaceuticals for Cancer Therapy,” Journal of Nuclear Medicine 63 (2022): 952-958.

[448] Y. Liu, T. Watabe, K. Kaneda-Nakashima, et al., “Fibroblast Activation Protein Targeted Therapy Using [(177)Lu]FAPI-46 Compared With [(225)Ac]FAPI-46 in a Pancreatic Cancer Model,” European Journal of Nuclear Medicine and Molecular Imaging 49 (2022): 871-880.

[449] S. Boinapally, A. Lisok, G. Lofland, et al., “Hetero-bivalent Agents Targeting FAP and PSMA,” European Journal of Nuclear Medicine and Molecular Imaging 49 (2022): 4369-4381.

[450] W. Huang, Y. Pang, Q. Liu, et al., “Development and Characterization of Novel FAP-Targeted Theranostic Pairs: A Bench-to-Bedside Study,” Research (Wash D C) 6 (2023): 0282.

[451] W. P. Fendler, K. M. Pabst, L. Kessler, et al., “Safety and Efficacy of 90Y-FAPI-46 Radioligand Therapy in Patients With Advanced Sarcoma and Other Cancer Entities,” Clinical Cancer Research 28 (2022): 4346-4353.

[452] T. Lindner, A. Altmann, S. Krämer, et al., “Design and Development of (99m)Tc-Labeled FAPI Tracers for SPECT Imaging and (188)Re Therapy,” Journal of Nuclear Medicine 61 (2020): 1507-1513.

[453] J. Ferdinandus, P. F. Costa, L. Kessler, et al., “Initial Clinical Experience With (90)Y-FAPI-46 Radioligand Therapy for Advanced-Stage Solid Tumors: A Case Series of 9 Patients,” Journal of Nuclear Medicine 63 (2022): 727-734.

[454] H. Fu, J. Huang, L. Sun, H. Wu, H. Chen, “FAP-Targeted Radionuclide Therapy of Advanced Radioiodine-Refractory Differentiated Thyroid Cancer with Multiple Cycles of 177 Lu-FAPI-46,” Clinical Nuclear Medicine 47 (2022): 906-907.

[455] S. Ballal, M. P. Yadav, E. S. Moon, et al., “First-in-Human Experience with 177Lu-DOTAGA.(SA.FAPi)2 Therapy in an Uncommon Case of Aggressive Medullary Thyroid Carcinoma Clinically Mimicking as Anaplastic Thyroid Cancer,” Clinical Nuclear Medicine 47 (2022): e444-e445.

[456] S. S. Banihashemian, M. Bayat, E. Pirayesh, G. Divband, A. Abolhosseini, M. E. Akbari, “First Experience of Radionuclide Therapy with 177Lu-FAPI-2286 in a Patient with Metastatic Mediastinal Sarcoma,” Clinical Nuclear Medicine 49 (2024): e334-e337.

[457] C. Kratochwil, F. L. Giesel, H. Rathke, et al., “[(153)Sm]Samarium-labeled FAPI-46 Radioligand Therapy in a Patient With Lung Metastases of a Sarcoma,” European Journal of Nuclear Medicine and Molecular Imaging 48 (2021): 3011-3013.

[458] Y. Dekempeneer, S. Massa, F. Santens, et al., “Preclinical Evaluation of a Radiotheranostic Single-Domain Antibody against Fibroblast Activation Protein α,” Journal of Nuclear Medicine 64 (2023): 1941-1948.

[459] S. Ballal, M. P. Yadav, S. Raju, et al., “[(177)Lu]Lu-DOTAGA.Glu.(FAPi)(2) Radionuclide Therapy: A New Treatment Option for Patients With Glioblastoma Multiforme,” Nuclear Medicine and Molecular Imaging 58 (2024): 32-34.

[460] L. Meng, J. Fang, L. Zhao, et al., “Rational Design and Pharmacomodulation of Protein-Binding Theranostic Radioligands for Targeting the Fibroblast Activation Protein,” Journal of Medicinal Chemistry 65 (2022): 8245-8257.

[461] L. Zhao, J. Chen, Y. Pang, et al., “Development of Fibroblast Activation Protein Inhibitor-Based Dimeric Radiotracers With Improved Tumor Retention and Antitumor Efficacy,” Molecular Pharmaceutics 19 (2022): 3640-3651.

[462] M. Assadi, S. J. Rekabpour, E. Jafari, et al., “Feasibility and Therapeutic Potential of 177Lu-Fibroblast Activation Protein Inhibitor-46 for Patients with Relapsed or Refractory Cancers: A Preliminary Study,” Clinical Nuclear Medicine 46 (2021): e523-e530.

[463] J. Mcconathy, M. Dhawan, A. H. Goenka, et al., “Abstract CT251: LuMIERE: A Phase 1/2 Study Investigating Safety, Pharmacokinetics, Dosimetry, and Preliminary Antitumor Activity of 177Lu-FAP-2286 in Patients With Advanced or Metastatic Solid Tumors,” Cancer Research 82 (2022): CT251-CT251.

[464] Z. Rao, Y. Zhang, L. Liu, M. Wang, C. Zhang, “(177)Lu]Lu-FAP-2286 Therapy in a Case of Right Lung Squamous Cell Carcinoma With Systemic Metastases,” European Journal of Nuclear Medicine and Molecular Imaging 50 (2023): 1266-1267.

[465] S. Ballal, M. P. Yadav, V. Kramer, et al., “A Theranostic Approach of [(68)Ga]Ga-DOTA.SA.FAPi PET/CT-guided [(177)Lu]Lu-DOTA.SA.FAPi Radionuclide Therapy in an End-stage Breast Cancer Patient: New Frontier in Targeted Radionuclide Therapy,” European Journal of Nuclear Medicine and Molecular Imaging 48 (2021): 942-944.

[466] M. P. Yadav, S. Ballal, M. Martin, et al., “Therapeutic Potential of [(177)Lu]Lu-DOTAGA-FAPi Dimers in Metastatic Breast Cancer Patients With Limited Treatment Options: Efficacy and Safety Assessment,” European Journal of Nuclear Medicine and Molecular Imaging 51 (2024): 805-819.

[467] S. Barashki, G. Divband, E. Askari, H. Amini, K. Aryana, “Fibroblast Activation Protein Inhibitor Imaging and Therapy in a Patient with Multiple Endocrine Neoplasia Type 2A Syndrome,” Clinical Nuclear Medicine 47 (2022): e284-e286.

[468] L. Zhao, Y. Pang, Y. Zhou, et al., “Antitumor Efficacy and Potential Mechanism of FAP-targeted Radioligand Therapy Combined With Immune Checkpoint Blockade,” Signal Transduction and Targeted Therapy 9 (2024): 142.

[469] S. Rafiq, C. S. Hackett, R. J. Brentjens, “Engineering Strategies to Overcome the Current Roadblocks in CAR T Cell Therapy,” Nature Reviews Clinical Oncology 17 (2020): 147-167.

[470] N. Muhammad, Q. Mao, H. Xia, “CAR T-cells for Cancer Therapy,” Biotechnology & Genetic Engineering Reviews 33 (2017): 190-226.

[471] L. Labanieh, R. G. Majzner, C. L. Mackall, “Programming CAR-T Cells to Kill Cancer,” Nature Biomedical Engineering 2 (2018): 377-391.

[472] L. Chen, F. Chen, J. Li, et al., “CAR-T Cell Therapy for Lung Cancer: Potential and Perspective,” Thorac Cancer 13 (2022): 889-899.

[473] R. Bughda, P. Dimou, R. R. D'Souza, A. Klampatsa, “Fibroblast Activation Protein (FAP)-Targeted CAR-T Cells: Launching an Attack on Tumor Stroma,” ImmunoTargets and Therapy 10 (2021): 313-323.

[474] L.-C. S. Wang, A. Lo, J. Scholler, et al., “Targeting Fibroblast Activation Protein in Tumor Stroma With Chimeric Antigen Receptor T Cells Can Inhibit Tumor Growth and Augment Host Immunity Without Severe Toxicity,” Cancer Immunology Research 2 (2014): 154-166.

[475] A. Curioni, C. Britschgi, S. Hiltbrunner, et al., “1226P—A Phase I Clinical Trial of Malignant Pleural Mesothelioma Treated With Locally Delivered Autologous Anti-FAP-targeted CAR T-cells,” Annals of Oncology 30 (2019): v501.

[476] H. Wu, X. Fu, Y. Zhai, S. Gao, X. Yang, G. Zhai, “Development of Effective Tumor Vaccine Strategies Based on Immune Response Cascade Reactions,” Advanced Healthcare Materials 10 (2021): e2100299.

[477] M. Saxena, S. H. van der Burg, C. J. M. Melief, N. Bhardwaj, “Therapeutic Cancer Vaccines,” Nature Reviews Cancer 21 (2021): 360-378.

[478] M. Peng, Y. Mo, Y. Wang, et al., “Neoantigen Vaccine: An Emerging Tumor Immunotherapy,” Molecular Cancer 18 (2019): 128.

[479] Y. Li, X. Ma, Y. Yue, et al., “Rapid Surface Display of mRNA Antigens by Bacteria-Derived Outer Membrane Vesicles for a Personalized Tumor Vaccine,” Advanced Materials 34 (2022): e2109984.

[480] M. Loeffler, “Targeting Tumor-associated Fibroblasts Improves Cancer Chemotherapy by Increasing Intratumoral Drug Uptake,” Journal of Clinical Investigation 116 (2006): 1955-1962.

[481] E. K. Duperret, A. Trautz, D. Ammons, et al., “Alteration of the Tumor Stroma Using a Consensus DNA Vaccine Targeting Fibroblast Activation Protein (FAP) Synergizes With Antitumor Vaccine Therapy in Mice,” Clinical Cancer Research 24 (2018): 1190-1201.

[482] D. Liao, Y. Luo, D. Markowitz, R. Xiang, R. A. Reisfeld, “Cancer Associated Fibroblasts Promote Tumor Growth and Metastasis by Modulating the Tumor Immune Microenvironment in a 4T1 Murine Breast Cancer Model,” PLoS ONE 4 (2009): e7965.

[483] I. A. Vathiotis, M. K. Moutafi, P. Divakar, et al., “Alpha-smooth Muscle Actin Expression in the Stroma Predicts Resistance to Trastuzumab in Patients With Early-stage HER2-positive Breast Cancer,” Clinical Cancer Research 27 (2021): 6156-6163.

[484] M. Murakami, M. J. Ernsting, E. Undzys, N. Holwell, W. D. Foltz, S.-D. Li, “Docetaxel Conjugate Nanoparticles That Target α-smooth Muscle Actin-expressing Stromal Cells Suppress Breast Cancer Metastasis,” Cancer Research 73 (2013): 4862-4871.

[485] M. Yang, J. Li, P. Gu, X. Fan, “The Application of Nanoparticles in Cancer Immunotherapy: Targeting Tumor Microenvironment,” Bioact Mater 6 (2021): 1973-1987.

[486] H. Venugopal, A. Hanna, C. Humeres, N. G. Frangogiannis, “Properties and Functions of Fibroblasts and Myofibroblasts in Myocardial Infarction,” Cells 11 (2022): 1386.

[487] G. Cao, X. Xuan, J. Hu, R. Zhang, H. Jin, H. Dong, “How Vascular Smooth Muscle Cell Phenotype Switching Contributes to Vascular Disease,” Cell Communication and Signaling 20 (2022): 180.

[488] X. Xu, T. Xia, “Recent Advances in Site-Specific Lipid Nanoparticles for mRNA Delivery,” ACS Nanoscience Au 3 (2023): 192-203.

[489] D. Song, Y. Zhao, Z. Wang, Q. Xu, “Tuning Lipid Nanoparticles for RNA Delivery to Extrahepatic Organs,” Advanced Materials 36 (2024): e2401445.

[490] H. Liao, J. Liao, L. Zeng, X. Cao, H. Fan, J. Chen, “Strategies for Organ-Targeted mRNA Delivery by Lipid Nanoparticles,” Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology 16 (2024): e2004.

[491] M. Alsaggar, D. Liu, “Organ-based Drug Delivery,” Journal of Drug Targeting 26 (2018): 385-397.

[492] M. Erkan, G. Adler, M. V. Apte, et al., “StellaTUM: Current Consensus and Discussion on Pancreatic Stellate Cell Research,” Gut 61 (2012): 172-178.

[493] M. V. Apte, J. S. Wilson, A. Lugea, S. J. Pandol, “A Starring Role for Stellate Cells in the Pancreatic Cancer Microenvironment,” Gastroenterology 144 (2013): 1210-1219.

[494] M. V. Apte, S. Park, P. A. Phillips, et al., “Desmoplastic Reaction in Pancreatic Cancer: Role of Pancreatic Stellate Cells,” Pancreas 29 (2004): 179-187.

[495] Y. Yu, K. Schuck, H. Friess, B. Kong, “Targeting Aggressive Fibroblasts to Enhance the Treatment of Pancreatic Cancer,” Expert Opinion on Therapeutic Targets 25 (2021): 5-13.

[496] F. E. M. Froeling, C. Feig, C. Chelala, et al., “Retinoic Acid-induced Pancreatic Stellate Cell Quiescence Reduces Paracrine Wnt-β-catenin Signaling to Slow Tumor Progression,” Gastroenterology 141 (2011): 1486-1497, e1481-1414.

[497] E. F. Carapuça, E. Gemenetzidis, C. Feig, et al., “Anti-stromal Treatment Together With Chemotherapy Targets Multiple Signalling Pathways in Pancreatic Adenocarcinoma,” Journal of Pathology 239 (2016): 286-296.

[498] H. M. Kocher, B. Basu, F. E. M. Froeling, et al., “Phase I Clinical Trial Repurposing all-trans Retinoic Acid as a Stromal Targeting Agent for Pancreatic Cancer,” Nature Communications 11 (2020): 4841.

[499] Y. Gao, J. Li, W. Cheng, et al., “Cross-tissue human Fibroblast Atlas Reveals Myofibroblast Subtypes With Distinct Roles in Immune Modulation,” Cancer Cell 42 (2024): 1764-1783. e1710.

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