Tumor-Associated Macrophages as Therapeutic Targets: Deciphering Interaction Networks and Advancing Clinical Translation

Abstract

Tumor-associated macrophages (TAMs) represent the most abundant immune cell population within the tumor microenvironment and are central drivers of malignant progression and treatment resistance. High TAMs infiltration in solid tumors consistently correlates with poor clinical outcomes, largely due to their role in establishing an immunosuppressive milieu that supports tumor growth, metastasis, and undermines the efficacy of chemotherapy, radiotherapy (RT), and immune checkpoint inhibitors. Although TAMs are well-recognized promoters of tumor progression, the development of effective strategies to therapeutically target them remains an unmet clinical need. In this review, we examine the multifaceted mechanisms through which TAMs contribute to malignancy, including phagocytic signaling modulation, metabolic reprogramming, exosomal communication, and crosstalk with other immune cells. We also evaluate three key therapeutic strategies: blocking TAMs recruitment and survival, reprogramming TAMs toward antitumor phenotypes, and the emerging approach of chimeric antigen receptor macrophage therapy. Furthermore, we highlight the synergistic potential of integrating TAMs-targeted strategies with conventional chemotherapy, RT, and immunotherapeutic approaches. By synthesizing current clinical evidence, this review aims to inform the rational design of next-generation TAMs-targeted interventions and to propose novel strategies for overcoming treatment resistance.

Keywords

immunotherapy / immune escape / tumor-associated macrophages / tumor microenvironment

References

[1] W. H. Fridman, L. Zitvogel, C. Sautès-Fridman, et al., “The Immune Contexture in Cancer Prognosis and Treatment,” Nature Reviews Clinical Oncology 14, no. 12 (2017): 717–734.

[2] D. Bruni, K. Angell Helen, and J. Galon, “The Immune Contexture and Immunoscore in Cancer Prognosis and Therapeutic Efficacy,” Nature Reviews Cancer 20, no. 11 (2020): 662–680.

[3] N. Cox, M. Pokrovskii, R. Vicario, et al., “Origins, Biology, and Diseases of Tissue Macrophages,” Annual Review of Immunology 39, no. 1 (2021): 313–344.

[4] S.-Y. Wu and K. Watabe, “The Roles of Microglia/Macrophages in Tumor Progression of Brain Cancer and Metastatic Disease,” Frontiers in Bioscience (Landmark Edition) 22 (2017): 1805.

[5] A. Christofides, L. Strauss, A. Yeo, et al., “The Complex Role of Tumor-Infiltrating Macrophages,” Nature Immunology 23, no. 8 (2022): 1148–1156.

[6] G. Teti, C. Biondo, and C. Beninati, “The Phagocyte, Metchnikoff, and the Foundation of Immunology,” Microbiology Spectrum 4, no. 2 (2016): 10.

[7] M. T. Silva and M. Correia-Neves, “Neutrophils and Macrophages: The Main Partners of Phagocyte Cell Systems,” Frontiers in Immunology 3 (2012): 174.

[8] S. Yona and S. Gordon, “From the Reticuloendothelial to Mononuclear Phagocyte System—the Unaccounted Years,” Frontiers in Immunology 6 (2015): 328.

[9] R. V. Furth, Z. A. Cohn, J. G. Hirsch, et al., “The Mononuclear Phagocyte System: A New Classification of Macrophages, Monocytes, and Their Precursor Cells,” Bulletin of the World Health Organization 46, no. 6 (1972): 845–852.

[10] T. Lazarov, S. Juarez-Carreño, N. Cox, et al., “Physiology and Diseases of Tissue-Resident Macrophages,” Nature 618, no. 7966 (2023): 698–707.

[11] E. G. Perdiguero and F. Geissmann, “The Development and Maintenance of Resident Macrophages,” Nature Immunology 17, no. 1 (2016): 2–8.

[12] E. Mass, I. Ballesteros, M. Farlik, et al., “Specification of Tissue-Resident Macrophages during Organogenesis,” Science 353 (2016): 6304.

[13] A. H. David, M. I. Katharine, and C. Pridans, “The Mononuclear Phagocyte System: The Relationship Between Monocytes and Macrophages,” Trends in Immunology 40, no. 2 (2019): 98–112.

[14] P. E. Gomez, K. Kay, and S. Christian, “The Origin of Tissue-Resident Macrophages: When an Erythro-Myeloid Progenitor Is an Erythro-Myeloid Progenitor,” Immunity 43 (2015): 1023–1024.

[15] L. van de Laar, W. Saelens, S. De Prijck, et al., “Yolk Sac Macrophages, Fetal Liver, and Adult Monocytes Can Colonize an Empty Niche and Develop Into Functional Tissue-Resident Macrophages,” Immunity 44, no. 4 (2016): 755–768.

[16] F. Ginhoux and M. Guilliams, “Tissue-Resident Macrophage Ontogeny and Homeostasis,” Immunity 44, no. 3 (2016): 439–449.

[17] S. De Schepper, S. Verheijden, J. Aguilera-Lizarraga, et al., “Self-Maintaining Gut Macrophages Are Essential for Intestinal Homeostasis,” Cell 175, no. 2 (2018): 400–415. e13.

[18] Q. Yang, N. Guo, Y. Zhou, et al., “The Role of Tumor-Associated Macrophages (Tams) in Tumor Progression and Relevant Advance in Targeted Therapy,” Acta Pharm Sin B 10, no. 11 (2020): 2156–2170.

[19] A. Mantovani, A. Sica, and M. Locati, “Macrophage Polarization Comes of Age,” Immunity 23, no. 4 (2005): 344–346.

[20] B. Bottazzi, E. Erba, N. Nobili, et al., “A Paracrine Circuit in the Regulation of the Proliferation of Macrophages Infiltrating Murine Sarcomas,” The Journal of Immunology 144, no. 6 (1990): 2409–2412.

[21] B.-Z. Qian and W. Pollard Jeffrey, “Macrophage Diversity Enhances Tumor Progression and Metastasis,” Cell 141, no. 1 (2010): 39–51.

[22] K. Movahedi, D. Laoui, C. Gysemans, et al., “Different Tumor Microenvironments Contain Functionally Distinct Subsets of Macrophages Derived From Ly6c (High) Monocytes,” Cancer Research 70, no. 14 (2010): 5728–5739.

[23] J. Pittet Mikael, O. Michielin, and D. Migliorini, “Clinical Relevance of Tumour-Associated Macrophages,” Nature reviews Clinical oncology 19, no. 6 (2022): 402–421.

[24] A. H. Klimp, E. G. E. De Vries, G. L. Scherphof, et al., “A Potential Role of Macrophage Activation in the Treatment of Cancer,” Critical reviews in oncology/hematology 44, no. 2 (2002): 143–161.

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

[26] J. Garbán Hermes and B. Bonavida, “Nitric Oxide Sensitizes Ovarian Tumor Cells to Fas-Induced Apoptosis,” Gynecologic Oncology 73, no. 2 (1999): 257–264.

[27] D. Duluc, M. Corvaisier, S. Blanchard, et al., “Interferon-Γ Reverses the Immunosuppressive and Protumoral Properties and Prevents the Generation of Human Tumor-Associated Macrophages,” International Journal of Cancer 125, no. 2 (2009): 367–373.

[28] S. Chen, W. T. Lai Seigmund, E. Brown Christine, et al., “Harnessing and Enhancing Macrophage Phagocytosis for Cancer Therapy,” Frontiers in Immunology 12 (2021): 635173.

[29] H. Bruns, M. Büttner, M. Fabri, et al., “Vitamin D–Dependent Induction of Cathelicidin in Human Macrophages Results in Cytotoxicity Against High-Grade B Cell Lymphoma,” Science Translational Medicine 7, no. 282 (2015): 282ra47.

[30] S. Das, E. Sarrou, S. Podgrabinska, et al., “Tumor Cell Entry Into the Lymph Node Is Controlled by Ccl1 Chemokine Expressed by Lymph Node Lymphatic Sinuses,” Journal of Experimental Medicine 210, no. 8 (2013): 1509–1528.

[31] P.-F. Ma, C.-C. Gao, J. Yi, et al., “Cytotherapy With M1-Polarized Macrophages Ameliorates Liver Fibrosis by Modulating Immune Microenvironment in Mice,” Journal of Hepatology 67, no. 4 (2017): 770–779.

[32] E. Cendrowicz, Z. Sas, E. Bremer, et al., “The Role of Macrophages in Cancer Development and Therapy,” Cancers 13, no. 08 (2021): 1946.

[33] C. E. Lewis and J. W. Pollard, “Distinct Role of Macrophages in Different Tumor Microenvironments,” Cancer Research 66, no. 2 (2006): 605–612.

[34] T. Mitsudomi and Y. Yatabe, “Epidermal Growth Factor Receptor in Relation to Tumor Development: Egfr Gene and Cancer,” Febs Journal 277, no. 2 (2010): 301–308.

[35] L. K. Huynh, C. J. Hipolito, and P. Ten Dijke, “A Perspective on the Development of Tgf-Β Inhibitors for Cancer Treatment,” Biomolecules 9, no. 11 (2019), https://doi.org/10.3390/biom9110743.

[36] C. Liu, W. Zhang, J. Wang, et al., “Tumor-Associated Macrophage-Derived Transforming Growth Factor-Β Promotes Colorectal Cancer Progression Through Hif1-Trib3 Signaling,” Cancer Science 112, no. 10 (2021): 4198–4207.

[37] C. Guruvayoorappan, “Tumor versus Tumor-Associated Macrophages: How Hot Is the Link?,” Integrative Cancer Therapies 7, no. 2 (2008): 90–95.

[38] P. Chen, Y. Huang, R. Bong, et al., “Tumor-Associated Macrophages Promote Angiogenesis and Melanoma Growth via Adrenomedullin in a Paracrine and Autocrine Manner,” Clinical Cancer Research 17, no. 23 (2011): 7230–7239.

[39] A. Castro Brandyn, P. Flanigan, A. Jahangiri, et al., “Macrophage Migration Inhibitory Factor Downregulation: A Novel Mechanism of Resistance to Anti-Angiogenic Therapy,” Oncogene 36, no. 26 (2017): 3749–3759.

[40] G. Zhang, X. Tao, B. Ji, et al., “Hypoxia-Driven M2-Polarized Macrophages Facilitate Cancer Aggressiveness and Temozolomide Resistance in Glioblastoma,” Oxid Med Cell Longev 2022 (2022): 1614336.

[41] Y. Komohara, Y. Fujiwara, K. Ohnishi, et al., “Tumor-Associated Macrophages: Potential Therapeutic Targets for Anti-Cancer Therapy,” Advanced drug delivery reviews 99 (2016): 180–185.

[42] K. Movahedi and J. O. A. Van Ginderachter, “The Ontogeny and Microenvironmental Regulation of Tumor-Associated Macrophages,” Antioxidants & Redox Signaling 25, no. 14 (2016): 775–791.

[43] W. Sun, F. Q. Wei, W. J. Li, et al., “A Positive-Feedback Loop Between Tumour Infiltrating Activated Treg Cells and Type 2-Skewed Macrophages Is Essential for Progression of Laryngeal Squamous Cell Carcinoma,” British Journal of Cancer 117, no. 11 (2017): 1631–1643.

[44] S. R. Gordon, R. L. Maute, B. W. Dulken, et al., “Pd-1 Expression by Tumour-Associated Macrophages Inhibits Phagocytosis and Tumour Immunity,” Nature 545, no. 7655 (2017): 495–499.

[45] W. Li, F. Wu, S. Zhao, et al., “Correlation Between Pd-1/Pd-L1 Expression and Polarization in Tumor-Associated Macrophages: A Key Player in Tumor Immunotherapy,” Cytokine & Growth Factor Reviews 67 (2022): 49–57.

[46] Y. Suhail, M. P. Cain, K. Vanaja, et al., “Systems Biology of Cancer Metastasis,” Cell Systems 9, no. 2 (2019): 109–127.

[47] S. Gerstberger, Q. Jiang, and K. Ganesh, “Metastasis,” Cell 186, no. 8 (2023): 1564–1579.

[48] D. Hanahan and R. A. Weinberg, “Hallmarks of Cancer: The Next Generation,” Cell 144, no. 5 (2011): 646–674.

[49] S. Valastyan and R. A. Weinberg, “Tumor Metastasis: Molecular Insights and Evolving Paradigms,” Cell 147, no. 2 (2011): 275–292.

[50] T. Baslan and J. Hicks, “Unravelling Biology and Shifting Paradigms in Cancer With Single-Cell Sequencing,” Nature Reviews Cancer 17, no. 9 (2017): 557–569.

[51] S. M. Morrissey, F. Zhang, C. Ding, et al., “Tumor-Derived Exosomes Drive Immunosuppressive Macrophages in a Pre-Metastatic Niche Through Glycolytic Dominant Metabolic Reprogramming,” Cell Metabolism 33, no. 10 (2021): 2040–2058. e10.

[52] X. W. Chen, T. J. Yu, J. Zhang, et al., “Cyp4a in Tumor-Associated Macrophages Promotes Pre-Metastatic Niche Formation and Metastasis,” Oncogene 36, no. 35 (2017): 5045–5057.

[53] M. Qiu, K. Huang, Y. Liu, et al., “Modulation of Intestinal Microbiota by Glycyrrhizic Acid Prevents High-Fat Diet-Enhanced Pre-Metastatic Niche Formation and Metastasis,” Mucosal Immunology 12, no. 4 (2019): 945–957.

[54] H. Kim, H. Chung, J. Kim, et al., “Macrophages-Triggered Sequential Remodeling of Endothelium-Interstitial Matrix to Form Pre-Metastatic Niche in Microfluidic Tumor Microenvironment,” Adv Sci (Weinh) 6, no. 11 (2019): 1900195.

[55] M. Umakoshi, S. Takahashi, G. Itoh, et al., “Macrophage-Mediated Transfer of Cancer-Derived Components to Stromal Cells Contributes to Establishment of a Pro-Tumor Microenvironment,” Oncogene 38, no. 12 (2019): 2162–2176.

[56] E. Nasrollahzadeh, S. Razi, M. Keshavarz-Fathi, et al., “Pro-Tumorigenic Functions of Macrophages at the Primary, Invasive and Metastatic Tumor Site,” Cancer Immunology, Immunotherapy 69, no. 9 (2020): 1673–1697.

[57] Y. Liu and X. Cao, “Characteristics and Significance of the Pre-Metastatic Niche,” Cancer Cell 30, no. 5 (2016): 668–681.

[58] M. Wang, Z. Qin, J. Wan, et al., “Tumor-Derived Exosomes Drive Pre-Metastatic Niche Formation in Lung via Modulating Ccl1(+) Fibroblast and Ccr8(+) Treg Cell Interactions,” Cancer Immunology, Immunotherapy 71, no. 11 (2022): 2717–2730.

[59] S. Liu, M. Jiang, Q. Zhao, et al., “Vascular Endothelial Growth Factor Plays a Critical Role in the Formation of the Pre-Metastatic Niche via Prostaglandin E2,” Oncology Reports 32, no. 6 (2014): 2477–2484.

[60] Y. Wang, Y. Li, J. Zhong, et al., “Tumor-Derived Cav-1 Promotes Pre-Metastatic Niche Formation and Lung Metastasis in Breast Cancer,” Theranostics 13, no. 5 (2023): 1684–1697.

[61] V. Catalano, A. Turdo, S. Di Franco, et al., “Tumor and Its Microenvironment: A Synergistic Interplay,” Seminars in Cancer Biology 23, no. 6 (2013): 522–532. Pt B.

[62] M. Werner-Klein, A. Grujovic, C. Irlbeck, et al., “Interleukin-6 Trans-Signaling Is a Candidate Mechanism to Drive Progression of Human Dccs during Clinical Latency,” Nature Communications 11, no. 1 (2020): 4977.

[63] T. Beltraminelli and M. De Palma, “Biology and Therapeutic Targeting of Tumour-Associated Macrophages,” The Journal of Pathology 250, no. 5 (2020): 573–592.

[64] G. Denardo David and B. Ruffell, “Macrophages as Regulators of Tumour Immunity and Immunotherapy,” Nature Reviews Immunology 19, no. 6 (2019): 369–382.

[65] A. Mantovani, F. Marchesi, A. Malesci, et al., “Tumour-Associated Macrophages as Treatment Targets in Oncology,” Nature Reviews Clinical Oncology 14, no. 7 (2017): 399–416.

[66] S. K. Biswas, “Metabolic Reprogramming of Immune Cells in Cancer Progression,” Immunity 43, no. 3 (2015): 435–449.

[67] J. Lin, Y. Chen, Z. Zhang, et al., “Calreticulin, a Potential Coregulator of Immune Checkpoints and Biomarker Associated With Tumor Microenvironment and Clinical Prognostic Significance in Breast Invasive Carcinoma,” Environmental Toxicology 39, no. 5 (2024): 2717–2731.

[68] L. Xiao, L. Zhang, C. Guo, et al., “Find Me and Eat Me Signals: Tools to Drive Phagocytic Processes for Modulating Antitumor Immunity,” Cancer Communications 44, no. 7 (2024): 791–832.

[69] Galvez-Cancino Felipe, P. Simpson Alexander, C. Costoya, et al., “Fcγ Receptors and Immunomodulatory Antibodies in Cancer,” Nature Reviews Cancer 24, no. 1 (2024): 51–71.

[70] I.-M. Kur and A. Weigert, “Phosphatidylserine Externalization as Immune Checkpoint in Cancer,” Pflügers Archiv-European Journal of Physiology 476, no. 12 (2024): 1789–1802.

[71] M. Feng, W. Jiang, B. Y. S. Kim, et al., “Phagocytosis Checkpoints as New Targets for Cancer Immunotherapy,” Nature Reviews Cancer 19, no. 10 (2019): 568–586.

[72] W. H. Fridman, L. Zitvogel, C. Sautès-Fridman, et al., “The Immune Contexture in Cancer Prognosis and Treatment,” Nature reviews Clinical oncology 14, no. 12 (2017): 717–734.

[73] J. Fucikova, R. Spisek, G. Kroemer, et al., “Calreticulin and Cancer,” Cell Research 31 (2021): 5–16.

[74] S. Basu, J. Binder Robert, T. Ramalingam, et al., “Cd91 Is a Common Receptor for Heat Shock Proteins Gp96, Hsp90, Hsp70, and Calreticulin,” Immunity 14, no. 3 (2001): 303–313.

[75] A. Ogden Carol, A. Decathelineau, R. Hoffmann Peter, et al., “C1q and Mannose Binding Lectin Engagement of Cell Surface Calreticulin and Cd91 Initiates Macropinocytosis and Uptake of Apoptotic Cells,” The Journal of Experimental Medicine 194, no. 6 (2001): 781–796.

[76] R. W. Vandivier, A. Ogden Carol, A. Fadok Valerie, et al., “Role of Surfactant Proteins a, D, and C1q in the Clearance of Apoptotic Cells in Vivo and in Vitro: Calreticulin and Cd91 as a Common Collectin Receptor Complex,” The Journal of Immunology 169, no. 7 (2002): 3978–3986.

[77] W. Pang Wendy, V. Pluvinage John, A. Price Elizabeth, et al., “Hematopoietic Stem Cell and Progenitor Cell Mechanisms in Myelodysplastic Syndromes,” Proceedings of the National Academy of Sciences 110, no. 8 (2013): 3011–3016.

[78] P. Chao Mark, S. Jaiswal, R. Weissman-Tsukamoto, et al., “Calreticulin Is the Dominant Pro-Phagocytic Signal on Multiple Human Cancers and Is Counterbalanced by Cd47,” Science Translational Medicine 2, no. 63 (2010): 63ra94–63ra94.

[79] I. Shachar, A. Barak, H. Lewinsky, et al., “Slamf Receptors on Normal and Malignant B Cells,” Clinical Immunology 204 (2019): 23–30.

[80] L. Gautier Emmanuel, T. Shay, J. Miller, et al., “Gene-Expression Profiles and Transcriptional Regulatory Pathways That Underlie the Identity and Diversity of Mouse Tissue Macrophages,” Nature Immunology 13, no. 11 (2012): 1118–1128.

[81] C. Miller Jennifer, D. Brown Brian, T. Shay, et al., “Deciphering the Transcriptional Network of the Dendritic Cell Lineage,” Nature Immunology 13, no. 9 (2012): 888–899.

[82] J. Chen, M.-C. Zhong, H. Guo, et al., “Slamf7 Is Critical for Phagocytosis of Haematopoietic Tumour Cells via Mac-1 Integrin,” Nature 544, no. 7651 (2017): 493–497.

[83] A. Aderem and D. M. Underhill, “Mechanisms of Phagocytosis in Macrophages,” Annual Review of Immunology 17, no. 1 (1999): 593–623.

[84] F. Nimmerjahn and J. V. Ravetch, “Fcγ Receptors as Regulators of Immune Responses,” Nature Reviews Immunology 8, no. 1 (2008): 34–47.

[85] J. E. Bakema and M. Van Egmond, “Fc Receptor-Dependent Mechanisms of Monoclonal Antibody Therapy of Cancer,” Fc Receptors (2014): 373–392.

[86] P. Bruhns, “Properties of Mouse and Human Igg Receptors and Their Contribution to Disease Models,” Blood, The Journal of the American Society of Hematology 119, no. 24 (2012): 5640–5649.

[87] M. Daëron, “Fc Receptor Biology,” Annual Review of Immunology 15, no. 1 (1997): 203–234.

[88] M. T. Crowley, P. S. Costello, C. J. Fitzer-Attas, et al., “A Critical Role for Syk in Signal Transduction and Phagocytosis Mediated by Fcγ Receptors on Macrophages,” Journal of Experimental Medicine 186, no. 7 (1997): 1027–1039.

[89] Y. Mao and C. Finnemann Silvia, “Regulation of Phagocytosis by Rho Gtpases,” Small GTPases 6, no. 2 (2015): 89–99.

[90] A. Getahun and J. C. Cambier, “Of Itim S, Itam S, and Itam Is: Revisiting Immunoglobulin Fc Receptor Signaling,” Immunological Reviews 268, no. 1 (2015): 66–73.

[91] A. Beers Stephen, R. French Ruth, C. Chan HT, et al., “Antigenic Modulation Limits the Efficacy of Anti-Cd20 Antibodies: Implications for Antibody Selection,” Blood, The Journal of the American Society of Hematology 115, no. 25 (2010): 5191–5201.

[92] A. Bergtold, D. Desai Dharmesh, A. Gavhane, et al., “Cell Surface Recycling of Internalized Antigen Permits Dendritic Cell Priming of B Cells,” Immunity 23, no. 5 (2005): 503–514.

[93] P. Budde, N. Bewarder, V. Weinrich, et al., “Tyrosine-Containing Sequence Motifs of the Human Immunoglobulin G Receptors Fcriib1 and Fcriib2 Essential for Endocytosis and Regulation of Calcium Flux in B Cells,” Journal of Biological Chemistry 269, no. 48 (1994): 30636–30644.

[94] S. Nagata, “Apoptosis and Clearance of Apoptotic Cells,” Annual Review of Immunology 36, no. 1 (2018): 489–517.

[95] V. A. Fadok, D. R. Voelker, P. A. Campbell, et al., “Exposure of Phosphatidylserine on the Surface of Apoptotic Lymphocytes Triggers Specific Recognition and Removal by Macrophages,” Journal Of Immunology (Baltimore, Md: 1950) 148, no. 7 (1992): 2207–2216.

[96] R. B. Birge, S. Boeltz, S. Kumar, et al., “Phosphatidylserine Is a Global Immunosuppressive Signal in Efferocytosis, Infectious Disease, and Cancer,” Cell Death & Differentiation 23, no. 6 (2016): 962–978.

[97] A. Leventis Peter and S. Grinstein, “The Distribution and Function of Phosphatidylserine in Cellular Membranes,” Annual Review of Biophysics 39, no. 1 (2010): 407–427.

[98] G. Van Meer, “Dynamic Transbilayer Lipid Asymmetry,” Cold Spring Harbor Perspectives in Biology 3, no. 5 (2011): a004671.

[99] A. Kharitonenkov, Z. Chen, I. Sures, et al., “A Family of Proteins That Inhibit Signalling Through Tyrosine Kinase Receptors,” Nature 386, no. 6621 (1997): 181–186.

[100] Y. Fujioka, T. Matozaki, T. Noguchi, et al., “A Novel Membrane Glycoprotein, Shps-1, That Binds the Sh2-Domain-Containing Protein Tyrosine Phosphatase Shp-2 in Response to Mitogens and Cell Adhesion,” Molecular and Cellular Biology 16, no. 12 (1996): 6887–6899.

[101] A. Veillette, E. Thibaudeau, and S. Latour, “High Expression of Inhibitory Receptor Shps-1 and Its Association With Protein-Tyrosine Phosphatase Shp-1 in Macrophages,” Journal of Biological Chemistry 273, no. 35 (1998): 22719–22728.

[102] Z. Jiang, H. Sun, J. Yu, et al., “Targeting Cd47 for Cancer Immunotherapy,” Journal of Hematology & Oncology 14, no. 1 (2021): 180.

[103] C. Jiang, H. Sun, Z. Jiang, et al., “Targeting the Cd47/Sirpα Pathway in Malignancies: Recent Progress, Difficulties and Future Perspectives,” Frontiers in Oncology 14 (2024): 1378647.

[104] L. R. Silverman, D. R. Mckenzie, B. L. Peterson, et al., “Further Analysis of Trials With Azacitidine in Patients With Myelodysplastic Syndrome: Studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B,” Journal of Clinical Oncology 24, no. 24 (2006): 3895–3903.

[105] L. R. Silverman, E. P. Demakos, B. L. Peterson, et al., “Randomized Controlled Trial of Azacitidine in Patients With the Myelodysplastic Syndrome: A Study of the Cancer and Leukemia Group B,” Journal of Clinical Oncology 20, no. 10 (2002): 2429–2440.

[106] A. Sallman David, M. Al Malki Monzr, S. Asch Adam, et al., “Magrolimab in Combination With Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes: Final Results of a Phase Ib Study,” Journal of Clinical Oncology 41, no. 15 (2023): 2815–2826.

[107] Z. Yang, Y. Peng, W. Guo, et al., “Pd-L1 and Cd47 Co-Expression Predicts Survival and Enlightens Future Dual-Targeting Immunotherapy in Non-Small Cell Lung Cancer,” Thorac Cancer 12, no. 11 (2021): 1743–1751.

[108] Y. C. Chen, W. Shi, J. J. Shi, et al., “Progress of Cd47 Immune Checkpoint Blockade Agents in Anticancer Therapy: A Hematotoxic Perspective,” Journal of Cancer Research and Clinical Oncology 148, no. 1 (2022): 1–14.

[109] Q. Chen, X. Guo, and W. Ma, “Opportunities and Challenges of Cd47-Targeted Therapy in Cancer Immunotherapy,” Oncology Research 32, no. 1 (2023): 49–60.

[110] I. Mellman, G. Coukos, and G. Dranoff, “Cancer Immunotherapy Comes of Age,” Nature 480, no. 7378 (2011): 480–489.

[111] L. Mazzarella, B. A. Duso, D. Trapani, et al., “The Evolving Landscape of ‘Next-Generation’ Immune Checkpoint Inhibitors: A Review,” European Journal of Cancer 117 (2019): 14–31.

[112] M. Moehler, H. Xiao, I. Blum Steven, et al., “Health-Related Quality of Life With Nivolumab Plus Chemotherapy versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From Checkmate 649,” Journal of Clinical Oncology 41, no. 35 (2023): 5388–5399.

[113] Y. J. Bang, Y. K. Kang, D. V. Catenacci, et al., “Pembrolizumab Alone or in Combination With Chemotherapy as First-Line Therapy for Patients With Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: Results From the Phase Ii Nonrandomized Keynote-059 Study,” Gastric Cancer 22, no. 4 (2019): 828–837.

[114] C. Robert, L. Thomas, I. Bondarenko, et al., “Ipilimumab Plus Dacarbazine for Previously Untreated Metastatic Melanoma,” New England Journal of Medicine 364, no. 26 (2011): 2517–2526.

[115] Y. Jiang, M. Chen, H. Nie, et al., “Pd-1 and Pd-L1 in Cancer Immunotherapy: Clinical Implications and Future Considerations,” Human Vaccines & Immunotherapeutics 15, no. 5 (2019): 1111–1122.

[116] Z. Zhu, H. Zhang, B. Chen, et al., “Pd-L1-Mediated Immunosuppression in Glioblastoma Is Associated With the Infiltration and M2-Polarization of Tumor-Associated Macrophages,” Frontiers in Immunology 11 (2020): 588552.

[117] H. Yang, Q. Zhang, M. Xu, et al., “Ccl2-Ccr2 Axis Recruits Tumor Associated Macrophages to Induce Immune Evasion Through Pd-1 Signaling in Esophageal Carcinogenesis,” Molecular Cancer 19, no. 1 (2020): 41.

[118] B. Tan, X. Shi, J. Zhang, et al., “Inhibition of Rspo-Lgr4 Facilitates Checkpoint Blockade Therapy by Switching Macrophage Polarization,” Cancer Research 78, no. 17 (2018): 4929–4942.

[119] N. Liu, J. Zhang, M. Yin, et al., “Inhibition of Xct Suppresses the Efficacy of Anti-Pd-1/L1 Melanoma Treatment Through Exosomal Pd-L1-Induced Macrophage M2 Polarization,” Molecular Therapy 29, no. 7 (2021): 2321–2334.

[120] W. Xie, L. J. Medeiros, S. Li, et al., “Pd-1/Pd-L1 Pathway and Its Blockade in Patients With Classic Hodgkin Lymphoma and Non-Hodgkin Large-Cell Lymphomas,” Current Hematologic Malignancy Reports 15, no. 4 (2020): 372–381.

[121] L. Xia, Y. Liu, and Y. Wang, “Pd-1/Pd-L1 Blockade Therapy in Advanced Non-Small-Cell Lung Cancer: Current Status and Future Directions,” The Oncologist 24, no. 1 (2019): S31–s41.

[122] K. Masuda, H. Horinouchi, M. Tanaka, et al., “Efficacy of Anti-Pd-1 Antibodies in Nsclc Patients With an Egfr Mutation and High Pd-L1 Expression,” Journal of Cancer Research and Clinical Oncology 147, no. 1 (2021): 245–251.

[123] D. J. Olson, Z. Eroglu, B. Brockstein, et al., “Pembrolizumab plus Ipilimumab Following Anti-Pd-1/L1 Failure in Melanoma,” Journal of Clinical Oncology 39, no. 24 (2021): 2647–2655.

[124] P. Du Rusquec, O. De Calbiac, and M. Robert, “Clinical Utility of Pembrolizumab in the Management of Advanced Solid Tumors: An Evidence-Based Review on the Emerging New Data,” Cancer Manag Res 11 (2019): 4297–4312.

[125] Y. Agata, A. Kawasaki, H. Nishimura, et al., “Expression of the Pd-1 Antigen on the Surface of Stimulated Mouse T and B Lymphocytes,” International Immunology 8, no. 5 (1996): 765–772.

[126] J. Inokuchi and M. Eto, “Profile of Pembrolizumab in the Treatment of Patients With Unresectable or Metastatic Urothelial Carcinoma,” Cancer Manag Res 11 (2019): 4519–4528.

[127] G. Kwok, T. C. Yau, J. W. Chiu, et al., “Pembrolizumab (Keytruda),” Human Vaccines & Immunotherapeutics 12, no. 11 (2016): 2777–2789.

[128] M. Reck, D. Rodríguez-Abreu, A. G. Robinson, et al., “Pembrolizumab versus Chemotherapy for Pd-L1-Positive Non-Small-Cell Lung Cancer,” New England Journal of Medicine 375, no. 19 (2016): 1823–1833.

[129] Y. Ishida, Y. Agata, K. Shibahara, et al., “Induced Expression of Pd-1, a Novel Member of the Immunoglobulin Gene Superfamily, Upon Programmed Cell Death,” Embo Journal 11, no. 11 (1992): 3887–3895.

[130] S. L. Topalian, J. M. Taube, and D. M. Pardoll, “Neoadjuvant Checkpoint Blockade for Cancer Immunotherapy,” Science 367, no. 6477 (2020), https://doi.org/10.1126/science.aax0182.

[131] V. Longo, O. Brunetti, A. Azzariti, et al., “Strategies to Improve Cancer Immune Checkpoint Inhibitors Efficacy, Other than Abscopal Effect: A Systematic Review,” Cancers (Basel) 11, no. 4 (2019), https://doi.org/10.3390/cancers11040539.

[132] T. N. Gide, J. S. Wilmott, R. A. Scolyer, et al., “Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Metastatic Melanoma,” Clinical Cancer Research 24, no. 6 (2018): 1260–1270.

[133] C. M. Fares, E. M. Van Allen, C. G. Drake, et al., “Mechanisms of Resistance to Immune Checkpoint Blockade: Why Does Checkpoint Inhibitor Immunotherapy Not Work for all Patients?,” American Society of Clinical Oncology Educational Book 39 (2019): 147–164.

[134] A. Carretero-González, D. Lora, I. Ghanem, et al., “Analysis of Response Rate With Anti Pd1/Pd-L1 Monoclonal Antibodies in Advanced Solid Tumors: A Meta-Analysis of Randomized Clinical Trials,” Oncotarget 9, no. 9 (2018): 8706–8715.

[135] Y. Nakamura, “Biomarkers for Immune Checkpoint Inhibitor-Mediated Tumor Response and Adverse Events,” Front Med (Lausanne) 6 (2019): 119.

[136] X. Chen, Q. Lu, H. Zhou, et al., “A Membrane-Associated Mhc-I Inhibitory Axis for Cancer Immune Evasion,” Cell 186, no. 18 (2023): 3903–3920. e21.

[137] K. Yamamoto, A. Venida, J. Yano, et al., “Autophagy Promotes Immune Evasion of Pancreatic Cancer by Degrading Mhc-I,” Nature 581, no. 7806 (2020): 100–105.

[138] K. Dhatchinamoorthy, J. D. Colbert, and K. L. Rock, “Cancer Immune Evasion Through Loss of Mhc Class I Antigen Presentation,” Frontiers in Immunology 12 (2021): 636568.

[139] X. Wu, T. Li, R. Jiang, et al., “Targeting Mhc-I Molecules for Cancer: Function, Mechanism, and Therapeutic Prospects,” Molecular Cancer 22, no. 1 (2023): 194.

[140] R. W. Lentz, M. D. Colton, S. S. Mitra, et al., “Innate Immune Checkpoint Inhibitors: The Next Breakthrough in Medical Oncology?,” Molecular Cancer Therapeutics 20, no. 6 (2021): 961–974.

[141] C. L. Dulberger, C. P. Mcmurtrey, A. Hölzemer, et al., “Human Leukocyte Antigen F Presents Peptides and Regulates Immunity Through Interactions With Nk Cell Receptors,” Immunity 46, no. 6 (2017): 1018–1029. e7.

[142] T. Zeller, I. A. Münnich, R. Windisch, et al., “Perspectives of Targeting Lilrb1 in Innate and Adaptive Immune Checkpoint Therapy of Cancer,” Frontiers in Immunology 14 (2023): 1240275.

[143] N. T. Young, E. C. Waller, R. Patel, et al., “The Inhibitory Receptor Lilrb1 Modulates the Differentiation and Regulatory Potential of Human Dendritic Cells,” Blood 111, no. 6 (2008): 3090–3096.

[144] X. Kang, J. Kim, M. Deng, et al., “Inhibitory Leukocyte Immunoglobulin-Like Receptors: Immune Checkpoint Proteins and Tumor Sustaining Factors,” Cell Cycle 15, no. 1 (2016): 25–40.

[145] A. Naji, C. Menier, G. Maki, et al., “Neoplastic B-Cell Growth Is Impaired by Hla-G/Ilt2 Interaction,” Leukemia 26, no. 8 (2012): 1889–1892.

[146] Z. Hu, Q. Zhang, Z. He, et al., “Mhc1/Lilrb1 Axis as an Innate Immune Checkpoint for Cancer Therapy,” Frontiers in Immunology 15 (2024): 1421092.

[147] D. T. W. Van, H.-M. Chen, P.-Y. Pan, et al., “Lilrb Receptor-Mediated Regulation of Myeloid Cell Maturation and Function,” Cancer Immunology, Immunotherapy 66 (2017): 1079–1087.

[148] T. Sinthuwiwat, S. Buranapraditkun, W. Kamolvisit, et al., “A Lilrb1 Variant With a Decreased Ability to Phosphorylate Shp-1 Leads to Autoimmune Diseases,” Scientific Reports 12, no. 1 (2022): 15420.

[149] P. Bruhns, F. Vely, O. Malbec, et al., “Molecular Basis of the Recruitment of the Sh2 Domain-Containing Inositol 5-Phosphatases Ship1 and Ship2 by Fcgamma Riib,” Journal of Biological Chemistry 275, no. 48 (2000): 37357–37364.

[150] E. Bernit, E. Jean, B. Marlot, et al., “Hla-F and Lilrb1 Genetic Polymorphisms Associated With Alloimmunisation in Sickle Cell Disease,” International Journal of Molecular Sciences 24, no. 17 (2023), https://doi.org/10.3390/ijms241713591.

[151] M. Daëron, S. Jaeger, and L. Du Pasquier, “Immunoreceptor Tyrosine-Based Inhibition Motifs: A Quest in the Past and Future,” Immunological Reviews 224 (2008): 11–43.

[152] J. Middelburg, S. Ghaffari, T. A. W. Schoufour, et al., “The Mhc-E Peptide Ligands for Checkpoint Cd94/Nkg2a Are Governed by Inflammatory Signals, Whereas Lilrb1/2 Receptors Are Peptide Indifferent,” Cell reports 42, no. 12 (2023).

[153] G.-Y. Chen, K. Brown Nicholas, P. Zheng, et al., “Siglec-G/10 in Self–Nonself Discrimination of Innate and Adaptive Immunity,” Glycobiology 24 (2014): 800–806.

[154] S. J. Pirruccello and L. TW, “The Human B Cell-Associated Antigen Cd24 Is a Single Chain Sialoglycoprotein,” Journal of immunology (Baltimore, Md: 1950) 136, no. 10 (1986): 3779–3784.

[155] T. Springer, G. Galfre, D. S. Secher, et al., “Monoclonal Xenogeneic Antibodies to Murine Cell Surface Antigens: Identification of Novel Leukocyte Differentiation Antigens,” European Journal of Immunology 8, no. 8 (1978): 539–551.

[156] A. Barkal Amira, E. Brewer Rachel, M. Markovic, et al., “Cd24 Signalling Through Macrophage Siglec-10 Is a Target for Cancer Immunotherapy,” Nature 572, no. 7769 (2019): 392–396.

[157] W. Chen, C. Han, B. Xie, et al., “Induction of Siglec-G by Rna Viruses Inhibits the Innate Immune Response by Promoting Rig-I Degradation,” Cell 152, no. 3 (2013): 467–478.

[158] G. Y. Chen, X. Chen, S. King, et al., “Amelioration of Sepsis by Inhibiting Sialidase-Mediated Disruption of the Cd24-Siglecg Interaction,” Nature Biotechnology 29, no. 5 (2011): 428–435.

[159] G. Y. Chen, J. Tang, P. Zheng, et al., “Cd24 and Siglec-10 Selectively Repress Tissue Damage-Induced Immune Responses,” Science 323, no. 5922 (2009): 1722–1725.

[160] T. Toubai, G. Hou, N. Mathewson, et al., “Siglec-G-Cd24 Axis Controls the Severity of Graft-Versus-Host Disease in Mice,” Blood 123, no. 22 (2014): 3512–3523.

[161] P. R. Crocker, J. C. Paulson, and A. Varki, “Siglecs and Their Roles in the Immune System,” Nature Reviews Immunology 7, no. 4 (2007): 255–266.

[162] C. L. Abram and C. A. Lowell, “Shp1 Function in Myeloid Cells,” J Leukoc Biol 102, no. 3 (2017): 657–675.

[163] J. Dietrich, M. Cella, and M. Colonna, “Ig-Like Transcript 2 (Ilt2)/Leukocyte Ig-Like Receptor 1 (Lir1) Inhibits Tcr Signaling and Actin Cytoskeleton Reorganization,” Journal of Immunology 166, no. 4 (2001): 2514–2521.

[164] A. A. Barkal, R. E. Brewer, M. Markovic, et al., “Cd24 Signalling Through Macrophage Siglec-10 Is a Target for Cancer Immunotherapy,” Nature 572, no. 7769 (2019): 392–396.

[165] P. A. Oldenborg, A. Zheleznyak, Y. F. Fang, et al., “Role of Cd47 as a Marker of Self on Red Blood Cells,” Science 288, no. 5473 (2000): 2051–2054.

[166] A. N. Barclay and T. K. Van Den Berg, “The Interaction Between Signal Regulatory Protein Alpha (Sirpα) and Cd47: Structure, Function, and Therapeutic Target,” Annual Review of Immunology 32 (2014): 25–50.

[167] R. Medzhitov and A. Janeway Jr Charles, “Decoding the Patterns of Self and Nonself by the Innate Immune System,” Science 296, no. 5566 (2002): 298–300.

[168] M. P. Chao, I. L. Weissman, and R. Majeti, “The Cd47-Sirpα Pathway in Cancer Immune Evasion and Potential Therapeutic Implications,” Current Opinion in Immunology 24, no. 2 (2012): 225–232.

[169] D. Leone Robert and D. Powell Jonathan, “Metabolism of Immune Cells in Cancer,” Nature Reviews Cancer 20, no. 9 (2020): 516–531.

[170] B. Yingjie, L. I. Wei, D. M. Kremer, et al., “Cancer Slc43a2 Alters T Cell Methionine Metabolism and Histone Methylation,” Nature 585, no. 7824 (2020): 277–282.

[171] D. Buck Michael, T. Sowell Ryan, M. Kaech Susan, et al., “Metabolic Instruction of Immunity,” Cell 169, no. 4 (2017): 570–586.

[172] A. Viola, F. Munari, R. Sánchez-Rodríguez, et al., “The Metabolic Signature of Macrophage Responses,” Frontiers in Immunology 10 (2019): 1462.

[173] Z. Cai, W. Li, M. Brenner, et al., “Branched-Chain Ketoacids Derived From Cancer Cells Modulate Macrophage Polarization and Metabolic Reprogramming,” Frontiers in Immunology 13 (2022): 966158.

[174] Q. Zhao, Z. Chu, L. Zhu, et al., “2-Deoxy-D-Glucose Treatment Decreases Anti-Inflammatory M2 Macrophage Polarization in Mice With Tumor and Allergic Airway Inflammation,” Frontiers in Immunology 8 (2017): 637.

[175] G. G. Chen, P. Y. M. Woo, S. C. P. Ng, et al., “Impact of Metformin on Immunological Markers: Implication in Its Anti-Tumor Mechanism,” Pharmacology & Therapeutics 213 (2020): 107585.

[176] S. Wang, R. Liu, Q. Yu, et al., “Metabolic Reprogramming of Macrophages during Infections and Cancer,” Cancer Letters 452 (2019): 14–22.

[177] P. Su, Q. Wang, E. Bi, et al., “Enhanced Lipid Accumulation and Metabolism Are Required for the Differentiation and Activation of Tumor-Associated Macrophages,” Cancer Research 80, no. 7 (2020): 1438–1450.

[178] Y. Chen, J. Zhang, W. Cui, et al., “Cd36, a Signaling Receptor and Fatty Acid Transporter That Regulates Immune Cell Metabolism and Fate,” Journal of Experimental Medicine 219, no. 6 (2022), https://doi.org/10.1084/jem.20211314.

[179] W. Xiang, R. Shi, X. Kang, et al., “Monoacylglycerol Lipase Regulates Cannabinoid Receptor 2-Dependent Macrophage Activation and Cancer Progression,” Nature Communications 9, no. 1 (2018): 2574.

[180] L. Liang, H. He, S. Jiang, et al., “Tiam2 Contributes to Osimertinib Resistance, Cell Motility, and Tumor-Associated Macrophage M2-Like Polarization in Lung Adenocarcinoma,” International Journal of Molecular Sciences 23, no. 18 (2022), https://doi.org/10.3390/ijms231810415.

[181] P. Salvador and R.-P. Sergio, “Macrophage Polarization and Reprogramming in Acute Inflammation: A Redox Perspective,” Antioxidants 11, no. 7 (2022): 1394.

[182] S. C. Huang, A. M. Smith, B. Everts, et al., “Metabolic Reprogramming Mediated by the Mtorc2-Irf4 Signaling Axis Is Essential for Macrophage Alternative Activation,” Immunity 45, no. 4 (2016): 817–830.

[183] R. Geiger, J. C. Rieckmann, T. Wolf, et al., “L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-Tumor Activity,” Cell 167, no. 3 (2016): 829–842. e13.

[184] M. M. Kaneda, K. S. Messer, N. Ralainirina, et al., “Pi3kγ Is a Molecular Switch That Controls Immune Suppression,” Nature 539, no. 7629 (2016): 437–442.

[185] P. Foubert, M. M. Kaneda, and J. A. Varner, “Pi3kγ Activates Integrin Α(4) and Promotes Immune Suppressive Myeloid Cell Polarization during Tumor Progression,” Cancer Immunology Research 5, no. 11 (2017): 957–968.

[186] M. M. Kaneda, P. Cappello, A. V. Nguyen, et al., “Macrophage Pi3kγ Drives Pancreatic Ductal Adenocarcinoma Progression,” Cancer Discovery 6, no. 8 (2016): 870–885.

[187] A. C. Thomas and J. T. Mattila, “Of Mice and Men: Arginine Metabolism in Macrophages,” Frontiers in Immunology 5 (2014): 479.

[188] M. Kaneda Megan, S. Messer Karen, R. Natacha, et al., “Pi3kγ Is a Molecular Switch That Controls Immune Suppression,” Nature 539, no. 7629 (2016): 437–442.

[189] J. Q. Zhang, S. Zeng, G. A. Vitiello, et al., “Macrophages and Cd8(+) T Cells Mediate the Antitumor Efficacy of Combined Cd40 Ligation and Imatinib Therapy in Gastrointestinal Stromal Tumors,” Cancer Immunology Research 6, no. 4 (2018): 434–447.

[190] P. S. Liu, Y. T. Chen, X. Li, et al., “Cd40 Signal Rewires Fatty Acid and Glutamine Metabolism for Stimulating Macrophage Anti-Tumorigenic Functions,” Nature Immunology 24, no. 3 (2023): 452–462.

[191] E. De Visser Karin and A. Joyce Johanna, “The Evolving Tumor Microenvironment: From Cancer Initiation to Metastatic Outgrowth,” Cancer Cell 41, no. 3 (2023): 374–403.

[192] J. Zuo, H. Yan, S. Qin, et al., “Extracellular Vesicles in Cancer Drug Resistance: Mechanistic Insights and Therapeutic Implications,” MedComm–Oncology 3, no. 4 (2024): e94.

[193] S. Baig Mirza, A. Roy, S. Rajpoot, et al., “Tumor-Derived Exosomes in the Regulation of Macrophage Polarization,” Inflammation Research 69 (2020): 435–451.

[194] F. Ruivo Carolina, B. Adem, M. Silva, et al., “The Biology of Cancer Exosomes: Insights and New Perspectives,” Cancer Research 77, no. 23 (2017): 6480–6488.

[195] A. Mori Marcelo, G. Ludwig Raissa, R. Garcia-Martin, et al., “Extracellular Mirnas: From Biomarkers to Mediators of Physiology and Disease,” Cell Metabolism 30, no. 4 (2019): 656–673.

[196] S. Zhao, Y. Mi, B. Guan, et al., “Tumor-Derived Exosomal Mir-934 Induces Macrophage M2 Polarization to Promote Liver Metastasis of Colorectal Cancer,” Journal of Hematology & Oncology 13 (2020): 1–19.

[197] H. Shinohara, Y. Kuranaga, M. Kumazaki, et al., “Regulated Polarization of Tumor-Associated Macrophages by Mir-145 via Colorectal Cancer–Derived Extracellular Vesicles,” The Journal of Immunology 199, no. 4 (2017): 1505–1515.

[198] D. Gerloff, J. Lützkendorf, K. C. Moritz Rose, et al., “Melanoma-Derived Exosomal Mir-125b-5p Educates Tumor Associated Macrophages (Tams) by Targeting Lysosomal Acid Lipase a (Lipa),” Cancers 12, no. 2 (2020): 464.

[199] T. Lee Jeannie and M. S. Bartolomei, “X-Inactivation, Imprinting, and Long Noncoding Rnas in Health and Disease,” Cell 152, no. 6 (2013): 1308–1323.

[200] A. Fatica and I. Bozzoni, “Long Non-Coding Rnas: New Players in Cell Differentiation and Development,” Nature Reviews Genetics 15, no. 1 (2014): 7–21.

[201] Y. He, X.-M. Meng, C. Huang, et al., “Long Noncoding Rnas: Novel Insights Into Hepatocelluar Carcinoma,” Cancer Letters 344, no. 1 (2014): 20–27.

[202] T. Kogure, K. Yan Irene, W.-L. Lin, et al., “Extracellular Vesicle–Mediated Transfer of a Novel Long Noncoding Rna Tuc339: A Mechanism of Intercellular Signaling in Human Hepatocellular Cancer,” Genes & Cancer 4, no. 7–8 (2013): 261–272.

[203] X. Li, Y. I. Lei, M. Wu, et al., “Regulation of Macrophage Activation and Polarization by Hcc-Derived Exosomal Lncrna Tuc339,” International Journal of Molecular Sciences 19, no. 10 (2018): 2958.

[204] Y. Liang, X. Song, Y. Li, et al., “Lncrna Bcrt1 Promotes Breast Cancer Progression by Targeting Mir-1303/Ptbp3 Axis,” Molecular Cancer 19 (2020): 1–20.

[205] L. S. Kristensen, T. Jakobsen, H. Hager, et al., “The Emerging Roles of Circrnas in Cancer and Oncology,” Nature Reviews Clinical Oncology 19, no. 3 (2022): 188–206.

[206] Q. Sun, X. Lei, and X. Yang, “Circrnas as Upstream Regulators of Mirna//Hmga2 Axis in Human Cancer,” Pharmacology & Therapeutics 263 (2024): 108711.

[207] Q. Lin, Q. Qi, S. Hou, et al., “Exosomal Circular Rna Hsa_Circ_007293 Promotes Proliferation, Migration, Invasion, and Epithelial-Mesenchymal Transition of Papillary Thyroid Carcinoma Cells Through Regulation of the Microrna-653-5p/Paired Box 6 Axis,” Bioengineered 12, no. 2 (2021): 10136–10149.

[208] T. Michel, F. Hentges, and J. Zimmer, “Consequences of the Crosstalk Between Monocytes/Macrophages and Natural Killer Cells,” Frontiers in Immunology 3 (2013): 403.

[209] S. Sivori, D. Pende, L. Quatrini, et al., “Nk Cells and Ilcs in Tumor Immunotherapy,” Molecular Aspects of Medicine 80 (2021): 100870.

[210] H. Gonzalez, C. Hagerling, and Z. Werb, “Roles of the Immune System in Cancer: From Tumor Initiation to Metastatic Progression,” Genes & Development 32, no. 19–20 (2018): 1267–1284.

[211] T. Krneta, A. Gillgrass, S. Poznanski, et al., “M2-Polarized and Tumor-Associated Macrophages Alter Nk Cell Phenotype and Function in a Contact-Dependent Manner,” Journal of Leucocyte Biology 101, no. 1 (2017): 285–295.

[212] S. Platonova, J. Cherfils-Vicini, D. Damotte, et al., “Profound Coordinated Alterations of Intratumoral Nk Cell Phenotype and Function in Lung Carcinoma,” Cancer Research 71, no. 16 (2011): 5412–5422.

[213] M. Kloss, P. Decker, M. Baltz Katrin, et al., “Interaction of Monocytes With Nk Cells Upon Toll-Like Receptor-Induced Expression of the Nkg2d Ligand Mica,” The Journal of Immunology 181, no. 10 (2008): 6711–6719.

[214] L. Peng, J. Zhang, Y. Teng, et al., “Tumor-Associated Monocytes/Macrophages Impair Nk-Cell Function via Tgfβ1 in Human Gastric Cancer,” Cancer Immunology Research 5, no. 3 (2017): 248–256.

[215] R. Castriconi, C. Cantoni, C. M. Della, et al., “Transforming Growth Factor Β1 Inhibits Expression of Nkp30 and Nkg2d Receptors: Consequences for the Nk-Mediated Killing of Dendritic Cells,” Proceedings of the National Academy of Sciences 100, no. 7 (2003): 4120–4125.

[216] M. Gallazzi, D. Baci, L. Mortara, et al., “Prostate Cancer Peripheral Blood Nk Cells Show Enhanced Cd9, Cd49a, Cxcr4, Cxcl8, Mmp-9 Production and Secrete Monocyte-Recruiting and Polarizing Factors,” Frontiers in Immunology 11 (2021): 586126.

[217] S. Malekghasemi, J. Majidi, A. Baghbanzadeh, et al., “Tumor-Associated Macrophages: Protumoral Macrophages in Inflammatory Tumor Microenvironment,” Advanced Pharmaceutical Bulletin 10, no. 4 (2020): 556.

[218] A. Ponzetta, R. Carriero, S. Carnevale, et al., “Neutrophils Driving Unconventional T Cells Mediate Resistance Against Murine Sarcomas and Selected Human Tumors,” Cell 178, no. 2 (2019): 346–360. e24.

[219] L. Wu and H.-F. Zhang Xiang, “Tumor-Associated Neutrophils and Macrophages—Heterogenous but Not Chaotic,” Frontiers in Immunology 11 (2020): 553967.

[220] J. Kim and J.-S. Bae, “Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment,” Mediators of Inflammation 1 (2016): 6058147.

[221] S.-L. Zhou, Z.-J. Zhou, Z.-Q. Hu, et al., “Tumor-Associated Neutrophils Recruit Macrophages and T-Regulatory Cells to Promote Progression of Hepatocellular Carcinoma and Resistance to Sorafenib,” Gastroenterology 150, no. 7 (2016): 1646–1658. e17.

[222] P. Tsou, H. Katayama, E. J. Ostrin, et al., “The Emerging Role of B Cells in Tumor Immunity,” Cancer Research 76, no. 19 (2016): 5597–5601.

[223] H. Nelson Brad, “Cd20+ B Cells: The Other Tumor-Infiltrating Lymphocytes,” The Journal of Immunology 185, no. 9 (2010): 4977–4982.

[224] J. Gunderson Andrew, M. M. Kaneda, T. Tsujikawa, et al., “Bruton Tyrosine Kinase–Dependent Immune Cell Cross-Talk Drives Pancreas Cancer,” Cancer Discovery 6, no. 3 (2016): 270–285.

[225] C. Fremd, F. Schuetz, C. Sohn, et al., “B Cell-Regulated Immune Responses in Tumor Models and Cancer Patients,” Oncoimmunology 2, no. 7 (2013): e25443.

[226] S. I. Wang, W. Liu, D. Ly, et al., “Tumor-Infiltrating B Cells: Their Role and Application in Anti-Tumor Immunity in Lung Cancer,” Cellular & Molecular Immunology 16, no. 1 (2019): 6–18.

[227] T. Audzevich, R. Bashford-Rogers, A. Mabbott Neil, et al., “Pre/Pro-B Cells Generate Macrophage Populations during Homeostasis and Inflammation,” Proceedings of the National Academy of Sciences 114, no. 20 (2017): E3954–E3963.

[228] S. R. Dannenmann, J. Thielicke, M. Stöckli, et al., “Tumor-Associated Macrophages Subvert T-Cell Function and Correlate With Reduced Survival in Clear Cell Renal Cell Carcinoma,” Oncoimmunology 2, no. 3 (2013): e23562.

[229] S. Gordon and F. O. Martinez, “Alternative Activation of Macrophages: Mechanism and Functions,” Immunity 32, no. 5 (2010): 593–604.

[230] Z. He and S. Zhang, “Tumor-Associated Macrophages and Their Functional Transformation in the Hypoxic Tumor Microenvironment,” Frontiers in Immunology 12 (2021): 741305.

[231] H. M. Knochelmann, C. J. Dwyer, S. R. Bailey, et al., “When Worlds Collide: Th17 and Treg Cells in Cancer and Autoimmunity,” Cellular & Molecular Immunology 15, no. 5 (2018): 458–469.

[232] D. Waniczek, Z. Lorenc, M. Śnietura, et al., “Tumor-Associated Macrophages and Regulatory T Cells Infiltration and the Clinical Outcome in Colorectal Cancer,” Archivum Immunologiae Et Therapiae Experimentalis 65, no. 5 (2017): 445–454.

[233] L. La Fleur, J. Botling, and F. He, “Targeting Marco and Il37r on Immunosuppressive Macrophages in Lung Cancer Blocks Regulatory T Cells and Supports Cytotoxic Lymphocyte Function,” Cancer Research 81, no. 4 (2021): 956–967.

[234] Q. Zhu, X. Wu, Y. Wu, et al., “Interaction Between Treg Cells and Tumor-Associated Macrophages in the Tumor Microenvironment of Epithelial Ovarian Cancer,” Oncology Reports 36, no. 6 (2016): 3472–3478.

[235] Q. Wu, W. Zhou, S. Yin, et al., “Blocking Triggering Receptor Expressed on Myeloid Cells-1-Positive Tumor-Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti-Programmed Cell Death Ligand 1 Resistance in Liver Cancer,” Hepatology 70, no. 1 (2019): 198–214.

[236] T. Fujimura, Y. Kambayashi, Y. Fujisawa, et al., “Tumor-Associated Macrophages: Therapeutic Targets for Skin Cancer,” Frontiers in oncology 8 (2018): 3.

[237] S. Furudate, T. Fujimura, Y. Kambayashi, et al., “Immunomodulatory Effect of Imiquimod Through Ccl22 Produced by Tumor-Associated Macrophages in B16f10 Melanomas,” Anticancer Research 37, no. 7 (2017): 3461–3471.

[238] D. Wang, L. Yang, D. Yue, et al., “Macrophage-Derived Ccl22 Promotes an Immunosuppressive Tumor Microenvironment via Il-8 in Malignant Pleural Effusion,” Cancer Letters 452 (2019): 244–253.

[239] J. M. Carbó, T. E. León, J. Font-Díaz, et al., “Pharmacologic Activation of Lxr Alters the Expression Profile of Tumor-Associated Macrophages and the Abundance of Regulatory T Cells in the Tumor Microenvironment,” Cancer Research 81, no. 4 (2021): 968–985.

[240] H. Raskov, A. Orhan, J. P. Christensen, et al., “Cytotoxic Cd8(+) T Cells in Cancer and Cancer Immunotherapy,” British Journal of Cancer 124, no. 2 (2021): 359–367.

[241] J. Reiser and A. Banerjee, “Effector, Memory, and Dysfunctional Cd8(+) T Cell Fates in the Antitumor Immune Response,” Journal of Immunology Research 2016 (2016): 8941260.

[242] E. Peranzoni, J. Lemoine, L. Vimeux, et al., “Macrophages Impede Cd8 T Cells From Reaching Tumor Cells and Limit the Efficacy of Anti-Pd-1 Treatment,” PNAS 115, no. 17 (2018): E4041–E4050.

[243] E. M. Garrido-Martin, T. W. P. Mellows, J. Clarke, et al., “M1(Hot) Tumor-Associated Macrophages Boost Tissue-Resident Memory T Cells Infiltration and Survival in Human Lung Cancer,” Journal for ImmunoTherapy of Cancer 8, no. 2 (2020), https://doi.org/10.1136/jitc-2020-000778.

[244] X. Dai, L. Lu, S. Deng, et al., “Usp7 Targeting Modulates Anti-Tumor Immune Response by Reprogramming Tumor-Associated Macrophages in Lung Cancer,” Theranostics 10, no. 20 (2020): 9332–9347.

[245] W. Fang, T. Zhou, H. Shi, et al., “Progranulin Induces Immune Escape in Breast Cancer via Up-Regulating Pd-L1 Expression on Tumor-Associated Macrophages (Tams) and Promoting Cd8(+) T Cell Exclusion,” Journal of Experimental & Clinical Cancer Research 40, no. 1 (2021): 4.

[246] H. Lin, S. Wei, E. M. Hurt, et al., “Host Expression of Pd-L1 Determines Efficacy of Pd-L1 Pathway Blockade-Mediated Tumor Regression,” Journal of Clinical Investigation 128, no. 2 (2018): 805–815.

[247] M. Pascual-García, E. Bonfill-Teixidor, E. Planas-Rigol, et al., “Lif Regulates Cxcl9 in Tumor-Associated Macrophages and Prevents Cd8(+) T Cell Tumor-Infiltration Impairing Anti-Pd1 Therapy,” Nature Communications 10, no. 1 (2019): 2416.

[248] J. S. Dolina, N. Van Braeckel-Budimir, G. D. Thomas, et al., “Cd8(+) T Cell Exhaustion in Cancer,” Frontiers in Immunology 12 (2021): 715234.

[249] I. S. Chan and A. J. Ewald, “The Changing Role of Natural Killer Cells in Cancer Metastasis,” Journal of Clinical Investigation 132, no. 6 (2022), https://doi.org/10.1172/jci143762.

[250] Y. Li, A. Sharma, J. Maciaczyk, et al., “Recent Development in Nkt-Based Immunotherapy of Glioblastoma: From Bench to Bedside,” International Journal of Molecular Sciences 23, no. 3 (2022), https://doi.org/10.3390/ijms23031311.

[251] H. Bayatipoor, S. Mehdizadeh, R. Jafarpour, et al., “Role of Nkt Cells in Cancer Immunotherapy-From Bench to Bed,” Medical Oncology 40, no. 1 (2022): 29.

[252] R. M. Mcewen-Smith, M. Salio, and V. Cerundolo, “The Regulatory Role of Invariant Nkt Cells in Tumor Immunity,” Cancer Immunology Research 3, no. 5 (2015): 425–435.

[253] K. Mortezaee and J. Majidpoor, “Nk and Cells With Nk-Like Activities in Cancer Immunotherapy-Clinical Perspectives,” Medical Oncology 39, no. 9 (2022): 131.

[254] L. Song, S. Asgharzadeh, J. Salo, et al., “Valpha24-Invariant Nkt Cells Mediate Antitumor Activity via Killing of Tumor-Associated Macrophages,” Journal of Clinical Investigation 119, no. 6 (2009): 1524–1536.

[255] E. A. Bae, H. Seo, I. K. Kim, et al., “Roles of Nkt Cells in Cancer Immunotherapy,” Archives of Pharmacal Research 42, no. 7 (2019): 543–548.

[256] R. Reantragoon, A. J. Corbett, I. G. Sakala, et al., “Antigen-Loaded Mr1 Tetramers Define T Cell Receptor Heterogeneity in Mucosal-Associated Invariant T Cells,” Journal of Experimental Medicine 210, no. 11 (2013): 2305–2320.

[257] L. Le Bourhis, E. Martin, I. Pguillet, et al., “Antimicrobial Activity of Mucosal-Associated Invariant T Cells,” Nature Immunology 11, no. 8 (2010): 701–708.

[258] S. Huang, E. Martin, S. Kim, et al., “Mr1 Antigen Presentation to Mucosal-Associated Invariant T Cells Was Highly Conserved in Evolution,” PNAS 106, no. 20 (2009): 8290–8295.

[259] L. Zheng, S. Qin, W. Si, et al., “Pan-Cancer Single-Cell Landscape of Tumor-Infiltrating T Cells,” Science 374, no. 6574 (2021): abe6474.

[260] C. Zheng, L. Zheng, J. K. Yoo, et al., “Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing,” Cell 169, no. 7 (2017): 1342–1356. e16.

[261] A. Kurioka, J. E. Ussher, C. Cosgrove, et al., “Mait Cells Are Licensed Through Granzyme Exchange to Kill Bacterially Sensitized Targets,” Mucosal Immunology 8, no. 2 (2015): 429–440.

[262] E. Billerbeck, Y. H. Kang, L. Walker, et al., “Analysis of Cd161 Expression on Human Cd8+ T Cells Defines a Distinct Functional Subset With Tissue-Homing Properties,” PNAS 107, no. 7 (2010): 3006–3011.

[263] N. A. Gherardin, L. Loh, L. Admojo, et al., “Enumeration, Functional Responses and Cytotoxic Capacity of Mait Cells in Newly Diagnosed and Relapsed Multiple Myeloma,” Scientific Reports 8, no. 1 (2018): 4159.

[264] T. Leng, H. D. Akther, C. P. Hackstein, et al., “Tcr and Inflammatory Signals Tune Human Mait Cells to Exert Specific Tissue Repair and Effector Functions,” Cell reports 28, no. 12 (2019): 3077–3091. e5.

[265] J. E. Ussher, M. Bilton, E. Attwod, et al., “Cd161++ Cd8+ T Cells, Including the Mait Cell Subset, Are Specifically Activated by Il-12+Il-18 in a Tcr-Independent Manner,” European Journal of Immunology 44, no. 1 (2014): 195–203.

[266] J. Dias, E. Leeansyah, and J. K. Sandberg, “Multiple Layers of Heterogeneity and Subset Diversity in Human Mait Cell Responses to Distinct Microorganisms and to Innate Cytokines,” PNAS 114, no. 27 (2017): E5434–E5443.

[267] J. Kelly, Y. Minoda, T. Meredith, et al., “Chronically Stimulated Human Mait Cells Are Unexpectedly Potent Il-13 Producers,” Immunology and Cell Biology 97, no. 8 (2019): 689–699.

[268] M. Duan, S. Goswami, J. Y. Shi, et al., “Activated and Exhausted Mait Cells Foster Disease Progression and Indicate Poor Outcome in Hepatocellular Carcinoma,” Clinical Cancer Research 25, no. 11 (2019): 3304–3316.

[269] B. Ruf, M. Bruhns, S. Babaei, et al., “Tumor-Associated Macrophages Trigger Mait Cell Dysfunction at the Hcc Invasive Margin,” Cell 186, no. 17 (2023): 3686–3705. e32.

[270] B. Silva-Santos, K. Serre, and H. Norell, “ΓδT Cells in Cancer,” Nature Reviews Immunology 15, no. 11 (2015): 683–691.

[271] B. Tamuli, S. Sharma, M. Patkar, et al., “Key Players of Immunosuppression in Epithelial Malignancies: Tumor-Infiltrating Myeloid Cells and ΓδT Cells,” Cancer Rep (Hoboken) 7, no. 5 (2024): e2066.

[272] J. A. Mathews, D. I. Kasahara, L. Ribeiro, et al., “ΓδT Cells Are Required for M2 Macrophage Polarization and Resolution of Ozone-Induced Pulmonary Inflammation in Mice,” PLoS ONE 10, no. 7 (2015): e0131236.

[273] M. Miyashita, T. Shimizu, E. Ashihara, et al., “Strategies to Improve the Antitumor Effect of ΓδT Cell Immunotherapy for Clinical Application,” International Journal of Molecular Sciences 22, no. 16 (2021): 8910.

[274] Y. Mao, S. Yin, J. Zhang, et al., “A New Effect of Il-4 on Human ΓδT Cells: Promoting Regulatory Vδ1 T Cells via Il-10 Production and Inhibiting Function of Vδ2 T Cells,” Cellular & Molecular Immunology 13, no. 2 (2016): 217–228.

[275] D. Wesch, D. Kabelitz, and H. H. Oberg, “Tumor Resistance Mechanisms and Their Consequences on ΓδT Cell Activation,” Immunological Reviews 298, no. 1 (2020): 84–98.

[276] D. I. Gabrilovich, V. Bronte, S. H. Chen, et al., “The Terminology Issue for Myeloid-Derived Suppressor Cells,” Cancer Research 67, no. 1 (2007): 425. author reply 26.

[277] J. C. Rodrigues, G. C. Gonzalez, L. Zhang, et al., “Normal Human Monocytes Exposed to Glioma Cells Acquire Myeloid-Derived Suppressor Cell-Like Properties,” Neuro-oncol 12, no. 4 (2010): 351–365.

[278] Y. Zhao, J. Du, and X. Shen, “Targeting Myeloid-Derived Suppressor Cells in Tumor Immunotherapy: Current, Future and Beyond,” Frontiers In Immunology 14 (2023): 1157537.

[279] T. Condamine, I. Ramachandran, J. I. Youn, et al., “Regulation of Tumor Metastasis by Myeloid-Derived Suppressor Cells,” Annual Review of Medicine 66 (2015): 97–110.

[280] J. E. Talmadge and D. I. Gabrilovich, “History of Myeloid-Derived Suppressor Cells,” Nature Reviews Cancer 13, no. 10 (2013): 739–752.

[281] D. Marvel and D. I. Gabrilovich, “Myeloid-Derived Suppressor Cells in the Tumor Microenvironment: Expect the Unexpected,” Journal of Clinical Investigation 125, no. 9 (2015): 3356–3364.

[282] S. Ugel, F. De Sanctis, S. Mandruzzato, et al., “Tumor-Induced Myeloid Deviation: When Myeloid-Derived Suppressor Cells Meet Tumor-Associated Macrophages,” Journal of Clinical Investigation 125, no. 9 (2015): 3365–3376.

[283] V. Kumar, S. Patel, E. Tcyganov, et al., “The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment,” Trends in Immunology 37, no. 3 (2016): 208–220.

[284] T. Celià-Terrassa and M. K. Jolly, “Cancer Stem Cells and Epithelial-to-Mesenchymal Transition in Cancer Metastasis,” Cold Spring Harbor Perspectives in Medicine 10, no. 7 (2020), https://doi.org/10.1101/cshperspect.a036905.

[285] T. Celià-Terrassa and Y. Kang, “Distinctive Properties of Metastasis-Initiating Cells,” Genes & Development 30, no. 8 (2016): 892–908.

[286] T. Oskarsson, E. Batlle, and J. Massagu, “Metastatic Stem Cells: Sources, Niches, and Vital Pathways,” Cell Stem Cell 14, no. 3 (2014): 306–321.

[287] L. Müller, A. Tunger, I. Plesca, et al., “Bidirectional Crosstalk Between Cancer Stem Cells and Immune Cell Subsets,” Frontiers in Immunology 11 (2020): 140.

[288] D. Bayik and J. D. Lathia, “Cancer Stem Cell-Immune Cell Crosstalk in Tumour Progression,” Nature Reviews Cancer 21, no. 8 (2021): 526–536.

[289] R. G. Stein, S. Ebert, L. Schlahsa, et al., “Cognate Nonlytic Interactions Between Cd8(+) T Cells and Breast Cancer Cells Induce Cancer Stem Cell-Like Properties,” Cancer Research 79, no. 7 (2019): 1507–1519.

[290] K. Li, H. Shi, B. Zhang, et al., “Myeloid-Derived Suppressor Cells as Immunosuppressive Regulators and Therapeutic Targets in Cancer,” Signal Transduct Target Ther 6, no. 1 (2021): 362.

[291] D. Roy, S. Bose, S. Pati, et al., “Gfi1/Hdac1-Axis Differentially Regulates Immunosuppressive Cd73 in Human Tumor-Associated Foxp3(+) Th17 and Inflammation-Linked Th17 Cells,” European Journal of Immunology 51, no. 5 (2021): 1206–1217.

[292] F. Zeppernick, R. Ahmadi, B. Campos, et al., “Stem Cell Marker Cd133 Affects Clinical Outcome in Glioma Patients,” Clinical Cancer Research 14, no. 1 (2008): 123–129.

[293] C. Raggi, H. S. Mousa, M. Correnti, et al., “Cancer Stem Cells and Tumor-Associated Macrophages: A Roadmap for Multitargeting Strategies,” Oncogene 35, no. 6 (2016): 671–682.

[294] T. M. Yeung, S. C. Gandhi, and W. F. Bodmer, “Hypoxia and Lineage Specification of Cell Line-Derived Colorectal Cancer Stem Cells,” PNAS 108, no. 11 (2011): 4382–4387.

[295] H. Lu, K. R. Clauser, W. L. Tam, et al., “A Breast Cancer Stem Cell Niche Supported by Juxtacrine Signalling From Monocytes and Macrophages,” Nature Cell Biology 16, no. 11 (2014): 1105–1117.

[296] S. Wan, E. Zhao, and I. Kryczek, “Tumor-Associated Macrophages Produce Interleukin 6 and Signal via Stat3 to Promote Expansion of Human Hepatocellular Carcinoma Stem Cells,” Gastroenterology 147, no. 6 (2014): 1393–1404.

[297] Y. Tan, M. Wang, Y. Zhang, et al., “Tumor-Associated Macrophages: A Potential Target for Cancer Therapy,” Frontiers in oncology 11 (2021): 693517.

[298] N. B. Hao, M. H. Lü, Y. H. Fan, et al., “Macrophages in Tumor Microenvironments and the Progression of Tumors,” Clinical & Developmental Immunology 2012 (2012): 948098.

[299] S. Luo, G. Yang, P. Ye, et al., “Macrophages Are a Double-Edged Sword: Molecular Crosstalk Between Tumor-Associated Macrophages and Cancer Stem Cells,” Biomolecules 12, no. 6 (2022), https://doi.org/10.3390/biom12060850.

[300] A. Wu, J. Wei, L. Y. Kong, et al., “Glioma Cancer Stem Cells Induce Immunosuppressive Macrophages/Microglia,” Neuro-Oncology 12, no. 11 (2010): 1113–1125.

[301] A. De Boeck, B. Y. Ahn, C. D'mello, et al., “Glioma-Derived Il-33 Orchestrates an Inflammatory Brain Tumor Microenvironment That Accelerates Glioma Progression,” Nature Communications 11, no. 1 (2020): 4997.

[302] K. Gabrusiewicz, X. Li, J. Wei, et al., “Glioblastoma Stem Cell-Derived Exosomes Induce M2 Macrophages and Pd-L1 Expression on Human Monocytes,” Oncoimmunology 7, no. 4 (2018): e1412909.

[303] P. Allavena, E. Digifico, and C. Belgiovine, “Macrophages and Cancer Stem Cells: A Malevolent Alliance,” Molecular Medicine 27, no. 1 (2021): 121.

[304] F. Zhang, P. Li, S. Liu, et al., “Β-Catenin-Ccl2 Feedback Loop Mediates Crosstalk Between Cancer Cells and Macrophages That Regulates Breast Cancer Stem Cells,” Oncogene 40, no. 39 (2021): 5854–5865.

[305] B. Guan, H. Li, J. Yao, et al., “Ccl3-Ccr5 Axis Promotes Cell Migration and Invasion of Colon Adenocarcinoma via Akt Signaling Pathway,” Environmental Toxicology 38, no. 1 (2023): 172–184.

[306] M. Novak, M. Koprivnikar Krajnc, B. Hrastar, et al., “Ccr5-Mediated Signaling Is Involved in Invasion of Glioblastoma Cells in Its Microenvironment,” International Journal of Molecular Sciences 21, no. 12 (2020), https://doi.org/10.3390/ijms21124199.

[307] N. N. V. Radharani, A. S. Yadav, R. Nimma, et al., “Tumor-Associated Macrophage Derived Il-6 Enriches Cancer Stem Cell Population and Promotes Breast Tumor Progression via Stat-3 Pathway,” Cancer Cell International 22, no. 1 (2022): 122.

[308] H. R. Cho, N. Kumari, and H. Thi Vu, “Increased Antiangiogenic Effect by Blocking Ccl2-Dependent Macrophages in a Rodent Glioblastoma Model: Correlation Study With Dynamic Susceptibility Contrast Perfusion Mri,” Scientific Reports 9, no. 1 (2019): 11085.

[309] C. T. Shih, C. W. Shiau, Y. L. Chen, et al., “Td-92, a Novel Erlotinib Derivative, Depletes Tumor-Associated Macrophages in Non-Small Cell Lung Cancer via Down-Regulation of Csf-1r and Enhances the Anti-Tumor Effects of Anti-Pd-1,” Cancer Letters 498 (2021): 142–151.

[310] C. Ngambenjawong, M. Cieslewicz, J. G. Schellinger, et al., “Synthesis and Evaluation of Multivalent M2pep Peptides for Targeting Alternatively Activated M2 Macrophages,” J Control Release 224 (2016): 103–111.

[311] J. Zhu, H. Huang, H. Chen, et al., “Plerixafor and Granulocyte-Colony-Stimulating Factor for Mobilization of Hematopoietic Stem Cells for Autologous Transplantation in Chinese Patients With Non-Hodgkin's Lymphoma: A Randomized Phase 3 Study,” Transfusion 58, no. 1 (2018): 81–87.

[312] 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, no. 6 (2020): 878–885.

[313] X. Peng, P. Hou, Y. Chen, et al., “Preclinical Evaluation of 3d185, a Novel Potent Inhibitor of Fgfr1/2/3 and Csf-1r, in Fgfr-Dependent and Macrophage-Dominant Cancer Models,” Journal of Experimental & Clinical Cancer Research 38, no. 1 (2019): 372.

[314] T. Fujiwara, M. A. Yakoub, A. Chandler, et al., “Csf1/Csf1r Signaling Inhibitor Pexidartinib (Plx3397) Reprograms Tumor-Associated Macrophages and Stimulates T-Cell Infiltration in the Sarcoma Microenvironment,” Molecular Cancer Therapeutics 20, no. 8 (2021): 1388–1399.

[315] M. H. Schleimann, M. L. Kobberø, L. K. Vibholm, et al., “Tlr9 Agonist Mgn1703 Enhances B Cell Differentiation and Function in Lymph Nodes,” EBioMedicine 45 (2019): 328–340.

[316] K. A. Reiss, M. G. Angelos, E. C. Dees, et al., “Car-Macrophage Therapy for Her2-Overexpressing Advanced Solid Tumors: A Phase 1 Trial,” Nature Medicine 31, no. 4 (2025): 1171–1182.

[317] Y. Chen, Z. Yu, X. Tan, et al., “Car-Macrophage: A New Immunotherapy Candidate Against Solid Tumors,” Biomedicine & Pharmacotherapy 139 (2021): 111605.

[318] 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, no. 5 (2003): 1639–1647.

[319] M. Provencio, E. Nadal, J. L. González-Larriba, et al., “Perioperative Nivolumab and Chemotherapy in Stage Iii Non-Small-Cell Lung Cancer,” New England Journal of Medicine 389, no. 6 (2023): 504–513.

[320] J. Naidoo, S. Antonia, Y. L. Wu, et al., “Brief Report: Durvalumab After Chemoradiotherapy in Unresectable Stage Iii Egfr-Mutant Nsclc: A Post Hoc Subgroup Analysis From Pacific,” Journal of Thoracic Oncology 18, no. 5 (2023): 657–663.

[321] H. A. Tawbi, D. Schadendorf, E. J. Lipson, et al., “Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma,” New England Journal of Medicine 386, no. 1 (2022): 24–34.

[322] C. G. Kim, M. H. Hong, D. Kim, et al., “A Phase Ii Open-Label Randomized Clinical Trial of Preoperative Durvalumab or Durvalumab Plus Tremelimumab in Resectable Head and Neck Squamous Cell Carcinoma,” Clinical Cancer Research 30, no. 10 (2024): 2097–2110.

[323] C. Gomez-Roca, P. Cassier, D. Zamarin, et al., “Anti-Csf-1r Emactuzumab in Combination With Anti-Pd-L1 Atezolizumab in Advanced Solid Tumor Patients Naïve or Experienced for Immune Checkpoint Blockade,” Journal for ImmunoTherapy of Cancer 10, no. 5 (2022): e004076.

[324] J. Boutilier Ava and F. Elsawa Sherine, “Macrophage Polarization States in the Tumor Microenvironment,” International Journal of Molecular Sciences 22, no. 13 (2021): 6995.

[325] C.-T. Shih, C.-W. Shiau, Y.-L. Chen, et al., “Td-92, a Novel Erlotinib Derivative, Depletes Tumor-Associated Macrophages in Non-Small Cell Lung Cancer via Down-Regulation of Csf-1r and Enhances the Anti-Tumor Effects of Anti-Pd-1,” Cancer Letters 498 (2021): 142–151.

[326] X. Li, W. Yao, Y. A. Yuan, et al., “Targeting of Tumour-Infiltrating Macrophages via Ccl2/Ccr2 Signalling as a Therapeutic Strategy Against Hepatocellular Carcinoma,” Gut 66, no. 1 (2017): 157–167.

[327] M. Li, L. He, J. Zhu, et al., “Targeting Tumor-Associated Macrophages for Cancer Treatment,” Cell & Bioscience 12, no. 1 (2022): 85.

[328] R. Cho Hye, N. Kumari, H. Thi Vu, et al., “Increased Antiangiogenic Effect by Blocking Ccl2-Dependent Macrophages in a Rodent Glioblastoma Model: Correlation Study With Dynamic Susceptibility Contrast Perfusion Mri,” Scientific Reports 9, no. 1 (2019): 11085.

[329] S. Gordon and R. Taylor Philip, “Monocyte and Macrophage Heterogeneity,” Nature Reviews Immunology 5 (2005): 953–964.

[330] C. Ngambenjawong, M. Cieslewicz, G. Schellinger Joan, et al., “Synthesis and Evaluation of Multivalent M2pep Peptides for Targeting Alternatively Activated M2 Macrophages,” Journal of Controlled Release 224 (2016): 103–111.

[331] B. Kakoschky, T. Pleli, C. Schmithals, et al., “Selective Targeting of Tumor Associated Macrophages in Different Tumor Models,” PLoS ONE 13, no. 2 (2018): e0193015.

[332] M. Cieslewicz, J. Tang, L. Yu Jonathan, et al., “Targeted Delivery of Proapoptotic Peptides to Tumor-Associated Macrophages Improves Survival,” Proceedings of the National Academy of Sciences 110, no. 40 (2013): 15919–15924.

[333] R. Wesolowski, N. Sharma, L. Reebel, et al., “Phase Ib Study of the Combination of Pexidartinib (Plx3397), a Csf-1r Inhibitor, and Paclitaxel in Patients With Advanced Solid Tumors,” Therapeutic Advances in Medical Oncology 11 (2019): 1758835919854238.

[334] J. Y. Ao, X. D. Zhu, Z. T. Chai, et al., “Colony-Stimulating Factor 1 Receptor Blockade Inhibits Tumor Growth by Altering the Polarization of Tumor-Associated Macrophages in Hepatocellular Carcinoma,” Molecular Cancer Therapeutics 16, no. 8 (2017): 1544–1554.

[335] A. Vidyarthi, N. Khan, T. Agnihotri, et al., “Tlr-3 Stimulation Skews M2 Macrophages to M1 Through Ifn-Αβ Signaling and Restricts Tumor Progression,” Frontiers in Immunology 9 (2018): 1650.

[336] K. Kapp, B. Volz, D. Oswald, et al., “Beneficial Modulation of the Tumor Microenvironment and Generation of Anti-Tumor Responses by Tlr9 Agonist Lefitolimod Alone and in Combination With Checkpoint Inhibitors,” Oncoimmunology 8, no. 12 (2019): e1659096.

[337] Z. Liu, Y. Xie, Y. Xiong, et al., “Tlr 7/8 Agonist Reverses Oxaliplatin Resistance in Colorectal Cancer via Directing the Myeloid-Derived Suppressor Cells to Tumoricidal M1-Macrophages,” Cancer Letters 469 (2020): 173–185.

[338] W. Nie, G. Wu, J. Zhang, et al., “Responsive Exosome Nano-Bioconjugates for Synergistic Cancer Therapy,” Angewandte Chemie International Edition 59, no. 5 (2020): 2018–2022.

[339] J. Wei, M. Hu, K. Huang, et al., “Roles of Proteoglycans and Glycosaminoglycans in Cancer Development and Progression,” International Journal of Molecular Sciences 21, no. 17 (2020), https://doi.org/10.3390/ijms21175983.

[340] J. Okrzeja, A. Karwowska, and A. Błachnio-Zabielska, “The Role of Obesity, Inflammation and Sphingolipids in the Development of an Abdominal Aortic Aneurysm,” Nutrients 14, no. 12 (2022): 2438.

[341] M. Liu, J. Liu, Z. Liang, et al., “Car-Macrophages and Car-T Cells Synergistically Kill Tumor Cells in Vitro,” Cells 11, no. 22 (2022): 3692.

[342] K. Hadiloo, S. Taremi, M. Heidari, et al., “The Car Macrophage Cells, a Novel Generation of Chimeric Antigen-Based Approach Against Solid Tumors,” Biomarker Research 11, no. 1 (2023): 103.

[343] S. Y. Li, Y. L. Guo, J. W. Tian, et al., “Anti-Tumor Strategies by Harnessing the Phagocytosis of Macrophages,” Cancers (Basel) 15, no. 10 (2023): 2717.

[344] Y. Liu, H. Tan, J. Dai, et al., “Targeting Macrophages in Cancer Immunotherapy: Frontiers and Challenges,” Journal of Advanced Research 76 (2025): 695–713.

[345] Y. R. Na, S. W. Kim, and S. H. Seok, “A New Era of Macrophage-Based Cell Therapy,” Experimental & Molecular Medicine 55, no. 9 (2023): 1945–1954.

[346] S. M. Abdin, D. Paasch, M. Morgan, et al., “Cars and Beyond: Tailoring Macrophage-Based Cell Therapeutics to Combat Solid Malignancies,” Journal for ImmunoTherapy of Cancer 9, no. 8 (2021): e002741.

[347] Q. Wang, X. Shao, Y. Zhang, et al., “Role of Tumor Microenvironment in Cancer Progression and Therapeutic Strategy,” Cancer medicine 12, no. 10 (2023): 11149–11165.

[348] M. Kciuk, E. B. Yahya, I. Mohamed, et al., “Recent Advances in Molecular Mechanisms of Cancer Immunotherapy,” Cancers (Basel) 15, no. 10 (2023): 2721.

[349] A. Chow, K. Perica, A. Klebanoff Christopher, et al., “Clinical Implications of T Cell Exhaustion for Cancer Immunotherapy,” Nature Reviews Clinical Oncology 19, no. 12 (2022): 775–790.

[350] Q. Deng, G. Han, N. Puebla-Osorio, et al., “Characteristics of Anti-Cd19 Car T Cell Infusion Products Associated With Efficacy and Toxicity in Patients With Large B Cell Lymphomas,” Nature Medicine 26, no. 12 (2020): 1878–1887.

[351] G. Ferrer, Á.-E. Damiana, and E. Manel, “Biological and Molecular Factors Predicting Response to Adoptive Cell Therapies in Cancer,” JNCI: Journal of the National Cancer Institute 114, no. 7 (2022): 930–939.

[352] A. Mantovani, P. Allavena, F. Marchesi, et al., “Macrophages as Tools and Targets in Cancer Therapy,” Nature Reviews Drug Discovery 21, no. 11 (2022): 799–820.

[353] S. Chen, F. U. H. Saeed Abdullah, Q. Liu, et al., “Macrophages in Immunoregulation and Therapeutics,” Signal Transduction and Targeted Therapy 8, no. 1 (2023): 207.

[354] C. Sloas, S. Gill, and M. Klichinsky, “Engineered Car-Macrophages as Adoptive Immunotherapies for Solid Tumors,” Frontiers in Immunology 12 (2021): 783305.

[355] Q. Liu, J. Li, H. Zheng, et al., “Adoptive Cellular Immunotherapy for Solid Neoplasms beyond Car-T,” Molecular Cancer 22, no. 1 (2023): 28.

[356] Z. Duan, Z. Li, Z. Wang, et al., “Chimeric Antigen Receptor Macrophages Activated Through Tlr4 or Ifn-Γ Receptors Suppress Breast Cancer Growth by Targeting Vegfr2,” Cancer Immunology, Immunotherapy 72, no. 10 (2023): 3243–3257.

[357] C. Sloas, S. Gill, and M. Klichinsky, “Engineered Car-Macrophages as Adoptive Immunotherapies for Solid Tumors,” Frontiers in Immunology 12 (2021): 783305.

[358] M. Klichinsky, M. Ruella, O. Shestova, et al., “Human Chimeric Antigen Receptor Macrophages for Cancer Immunotherapy,” Nature Biotechnology 38, no. 8 (2020): 947–953.

[359] Z. Niu, G. Chen, W. Chang, et al., “Chimeric Antigen Receptor-Modified Macrophages Trigger Systemic Anti-Tumour Immunity,” Journal of Pathology 253, no. 3 (2021): 247–257.

[360] L. Zhang, L. Tian, X. Dai, et al., “Pluripotent Stem Cell-Derived Car-Macrophage Cells With Antigen-Dependent Anti-Cancer Cell Functions,” Journal of Hematology & Oncology 13, no. 1 (2020): 153.

[361] Y. Chen, X. Zhu, H. Liu, et al., “The Application of Her2 and Cd47 Car-Macrophage in Ovarian Cancer,” Journal of Translational Medicine 21, no. 1 (2023): 654.

[362] G. Ferrer, D. Álvarez-Errico, and M. Esteller, “Biological and Molecular Factors Predicting Response to Adoptive Cell Therapies in Cancer,” JNCI: Journal of the National Cancer Institute 114, no. 7 (2022): 930–939.

[363] L. Labanieh and C. L. Mackall, “Car Immune Cells: Design Principles, Resistance and the Next Generation,” Nature 614, no. 7949 (2023): 635–648.

[364] D. J. Irvine, M. V. Maus, D. J. Mooney, et al., “The Future of Engineered Immune Cell Therapies,” Science 378, no. 6622 (2022): 853–858.

[365] R. Na Yi, W. Kim Sang, and H. Seok Seung, “A New Era of Macrophage-Based Cell Therapy,” Experimental & Molecular Medicine 55, no. 9 (2023): 1945–1954.

[366] C. He, J. Mansilla-Soto, N. Khanra, et al., “Cd19 Car Antigen Engagement Mechanisms and Affinity Tuning,” Science Immunology 8, no. 81 (2023): eadf1426.

[367] X. Wang, S. Su, Y. Zhu, et al., “Metabolic Reprogramming via Acod1 Depletion Enhances Function of Human Induced Pluripotent Stem Cell-Derived Car-Macrophages in Solid Tumors,” Nature Communications 14, no. 1 (2023): 5778.

[368] W. Zhang, Q. Han, Y. Ding, et al., “Bcl6 Drives Stem-Like Memory Macrophages Differentiation to Foster Tumor Progression,” Cellular and Molecular Life Sciences 80, no. 1 (2022): 14.

[369] J. H. Cho, J. J. Collins, and W. W. Wong, “Universal Chimeric Antigen Receptors for Multiplexed and Logical Control of T Cell Responses,” Cell 173, no. 6 (2018): 1426–1438. e11.

[370] J. Kwon, J. Kang, A. Jo, et al., “Single-Cell Mapping of Combinatorial Target Antigens for Car Switches Using Logic Gates,” Nature Biotechnology 41 (2023): 1593–1605. 11.

[371] D. Xue, S. Lu, H. Zhang, et al., “Induced Pluripotent Stem Cell-Derived Engineered T Cells, Natural Killer Cells, Macrophages, and Dendritic Cells in Immunotherapy,” Trends in Biotechnology 41, no. 7 (2023): 907–922.

[372] S. Ferrari, E. Valeri, A. Conti, et al., “Genetic Engineering Meets Hematopoietic Stem Cell Biology for Next-Generation Gene Therapy,” Cell Stem Cell 30, no. 5 (2023): 549–570.

[373] J. Li, P. Chen, and W. Ma, “The Next Frontier in Immunotherapy: Potential and Challenges of Car-Macrophages,” Experimental hematology & oncology 13, no. 1 (2024): 76.

[374] K. T. Roybal and W. A. Lim, “Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities,” Annual Review of Immunology 35 (2017): 229–253.

[375] P. Yousefpour, K. Ni, and D. J. Irvine, “Targeted Modulation of Immune Cells and Tissues Using Engineered Biomaterials,” Nat Rev Bioeng 1, no. 2 (2023): 107–124.

[376] E. M. Bressler, S. Adams, R. Liu, et al., “Boolean Logic in Synthetic Biology and Biomaterials: Towards Living Materials in Mammalian Cell Therapeutics,” Clinical and Translational Medicine 13, no. 7 (2023): e1244.

[377] L. Ma, A. Hostetler, D. M. Morgan, et al., “Vaccine-Boosted Car T Crosstalk With Host Immunity to Reject Tumors With Antigen Heterogeneity,” Cell 186, no. 15 (2023): 3148–3165. e20.

[378] M. E. Rodriguez-Ruiz, I. Vitale, K. J. Harrington, et al., “Immunological Impact of Cell Death Signaling Driven by Radiation on the Tumor Microenvironment,” Nature Immunology 21, no. 2 (2020): 120–134.

[379] Q. Wang, Y. Wang, J. Ding, et al., “A Bioorthogonal System Reveals Antitumour Immune Function of Pyroptosis,” Nature 579, no. 7799 (2020): 421–426.

[380] L. Galluzzi, J. Humeau, A. Buqu, et al., “Immunostimulation With Chemotherapy in the Era of Immune Checkpoint Inhibitors,” Nature Reviews Clinical Oncology 17, no. 12 (2020): 725–741.

[381] T. Sklarz, P. Guan, M. Gohil, et al., “Mtorc2 Regulates Multiple Aspects of Nkt-Cell Development and Function,” European Journal of Immunology 47, no. 3 (2017): 516–526.

[382] D. Samarkanova, S. Cox, D. Hernandez, et al., “Cord Blood Platelet Rich Plasma Derivatives for Clinical Applications in Non-Transfusion Medicine,” Frontiers in immunology 11 (2020): 942.

[383] B. Motais, S. Charvátová, Z. Walek, et al., “Selection, Expansion, and Unique Pretreatment of Allogeneic Human Natural Killer Cells With Anti-Cd38 Monoclonal Antibody for Efficient Multiple Myeloma Treatment,” Cells 10, no. 5 (2021), https://doi.org/10.3390/cells10050967.

[384] L. J. Burns, D. J. Weisdorf, T. E. Defor, et al., “Enhancement of the Anti-Tumor Activity of a Peripheral Blood Progenitor Cell Graft by Mobilization With Interleukin 2 Plus Granulocyte Colony-Stimulating Factor in Patients With Advanced Breast Cancer,” Experimental Hematology 28, no. 1 (2000): 96–103.

[385] Y. M. Liao, T. H. Hung, J. K. Tung, et al., “Low Expression of Il-15 and Nkt in Tumor Microenvironment Predicts Poor Outcome of Mycn-Non-Amplified Neuroblastoma,” J Pers Med 11, no. 2 (2021), https://doi.org/10.3390/jpm11020122.

[386] A. Heczey, A. N. Courtney, A. Montalbano, et al., “Anti-Gd2 Car-Nkt Cells in Patients With Relapsed or Refractory Neuroblastoma: An Interim Analysis,” Nature Medicine 26, no. 11 (2020): 1686–1690.

[387] S. M. Chang and M. G. Vander Heiden, “Inhibiting Gluttony in Cancer,” Cell Chem Biol 29, no. 3 (2022): 353–355.

[388] M. Mueckler and B. Thorens, “The Slc2 (Glut) Family of Membrane Transporters,” Molecular Aspects of Medicine 34, no. 2–3 (2013): 121–138.

[389] T. Robichaud, A. N. Appleyard, R. B. Herbert, et al., “Determinants of Ligand Binding Affinity and Cooperativity at the Glut1 Endofacial Site,” Biochemistry 50, no. 15 (2011): 3137–3148.

[390] G. Wang, Y. Lai, X. Chen, et al., “Hexokinase 2 Promotes Tumor Development and Progression,” American Journal of Cancer Research 15, no. 10 (2025): 4499–4515.

[391] F. Baenke, B. Peck, H. Miess, et al., “Hooked on Fat: The Role of Lipid Synthesis in Cancer Metabolism and Tumour Development,” Disease Models & Mechanisms 6, no. 6 (2013): 1353–1363.

[392] J. A. Menendez and R. Lupu, “Fatty Acid Synthase and the Lipogenic Phenotype in Cancer Pathogenesis,” Nature Reviews Cancer 7, no. 10 (2007): 763–777.

[393] C. Liu, M. Chikina, R. Deshpande, et al., “Treg Cells Promote the Srebp1-Dependent Metabolic Fitness of Tumor-Promoting Macrophages via Repression of Cd8(+) T Cell-Derived Interferon-Γ,” Immunity 51, no. 2 (2019): 381–397. e6.

[394] Q. Zhang, H. Wang, C. Mao, et al., “Fatty Acid Oxidation Contributes to Il-1β Secretion in M2 Macrophages and Promotes Macrophage-Mediated Tumor Cell Migration,” Molecular Immunology 94 (2018): 27–35.

[395] F. Hossain, A. A. Al-Khami, D. Wyczechowska, et al., “Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies,” Cancer Immunology Research 3, no. 11 (2015): 1236–1247.

[396] V. Cruzat, M. Macedo Rogero, K. Noel Keane, et al., “Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation,” Nutrients 10, no. 11 (2018), https://doi.org/10.3390/nu10111564.

[397] B. J. Altman, Z. E. Stine, and C. V. Dang, “From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy,” Nature Reviews Cancer 16, no. 11 (2016): 749.

[398] A. K. Jha, S. C. Huang, A. Sergushichev, et al., “Network Integration of Parallel Metabolic and Transcriptional Data Reveals Metabolic Modules That Regulate Macrophage Polarization,” Immunity 42, no. 3 (2015): 419–430.

[399] P. S. Liu, H. Wang, X. Li, et al., “Α-Ketoglutarate Orchestrates Macrophage Activation Through Metabolic and Epigenetic Reprogramming,” Nature Immunology 18, no. 9 (2017): 985–994.

[400] E. M. Palmieri, A. Menga, R. Martín-Pérez, et al., “Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages Toward an M1-Like Phenotype and Inhibits Tumor Metastasis,” Cell reports 20, no. 7 (2017): 1654–1666.

[401] J. M. Matés, F. J. Di Paola, J. A. Campos-Sandoval, et al., “Therapeutic Targeting of Glutaminolysis as an Essential Strategy to Combat Cancer,” Seminars in Cell & Developmental Biology 98 (2020): 34–43.

[402] G. Ma, Z. Zhang, P. Li, et al., “Reprogramming of Glutamine Metabolism and Its Impact on Immune Response in the Tumor Microenvironment,” Cell Communication and Signaling 20, no. 1 (2022): 114.

[403] R. Yadav, A. V. Singh, S. Kushwaha, et al., “Emerging Role of Exosomes as a Liquid Biopsy Tool for Diagnosis, Prognosis & Monitoring Treatment Response of Communicable & Non-Communicable Diseases,” Indian Journal of Medical Research 159, no. 2 (2024): 163–180.

[404] S. Li, M. Yi, B. Dong, et al., “The Role of Exosomes in Liquid Biopsy for Cancer Diagnosis and Prognosis Prediction,” International Journal of Cancer 148, no. 11 (2021): 2640–2651.

[405] B. Corradetti, D. Gonzalez, I. Mendes Pinto, et al., “Editorial: Exosomes as Therapeutic Systems,” Frontiers in Cell and Developmental Biology 9 (2021): 714743.

[406] M. Li, S. Li, C. Du, et al., “Exosomes From Different Cells: Characteristics, Modifications, and Therapeutic Applications,” European Journal of Medicinal Chemistry 207 (2020): 112784.

[407] A. T. H. Wu, P. Srivastava, V. K. Yadav, et al., “Ovatodiolide, Isolated From Anisomeles Indica, Suppresses Bladder Carcinogenesis Through Suppression of Mtor/Β-Catenin/Cdk6 and Exosomal Mir-21 Derived From M2 Tumor-Associated Macrophages,” Toxicology and Applied Pharmacology 401 (2020): 115109.

[408] À. M. Bellmunt, L. López-Puerto, J. Lorente, et al., “Involvement of Extracellular Vesicles in the Macrophage-Tumor Cell Communication in Head and Neck Squamous Cell Carcinoma,” PLoS ONE 14, no. 11 (2019): e0224710.

[409] K. Trajkovic, C. Hsu, S. Chiantia, et al., “Ceramide Triggers Budding of Exosome Vesicles Into Multivesicular Endosomes,” Science 319 (2008): 5867.

[410] R. Tenchov, J. M. Sasso, X. Wang, et al., “Exosomes─Nature's Lipid Nanoparticles, a Rising Star in Drug Delivery and Diagnostics,” ACS Nano 16, no. 11 (2022): 17802–17846.

[411] D. Wu, Q. Chen, X. Chen, et al., “The Blood-Brain Barrier: Structure, Regulation, and Drug Delivery,” Signal Transduct Target Ther 8, no. 1 (2023): 217.

[412] Y. Zhang, Q. Liu, X. Zhang, et al., “Recent Advances in Exosome-Mediated Nucleic Acid Delivery for Cancer Therapy,” J Nanobiotechnology 20, no. 1 (2022): 279.

[413] G. R. Gunassekaran, S. M. Poongkavithai Vadevoo, M. C. Baek, et al., “M1 Macrophage Exosomes Engineered to Foster M1 Polarization and Target the Il-4 Receptor Inhibit Tumor Growth by Reprogramming Tumor-Associated Macrophages Into M1-Like Macrophages,” Biomaterials 278 (2021): 121137.

[414] L. Xiao, U. Erb, K. Zhao, et al., “Efficacy of Vaccination With Tumor-Exosome Loaded Dendritic Cells Combined With Cytotoxic Drug Treatment in Pancreatic Cancer,” Oncoimmunology 6, no. 6 (2017): e1319044.

[415] B. Laura, C. Marie-May, W. Jeffrey, et al., “Cessation of Ccl2 Inhibition Accelerates Breast Cancer Metastasis by Promoting Angiogenesis,” Nature 515, no. 7525 (2014): 130–133.

[416] R. Kalluri and M. Zeisberg, “Fibroblasts in Cancer,” Nature Reviews Cancer 6, no. 5 (2006): 392–401.

[417] S. E. Kuzet and C. Gaggioli, “Fibroblast Activation in Cancer: When Seed Fertilizes Soil,” Cell and Tissue Research 365, no. 3 (2016): 607–619.

[418] H. Yamaguchi and R. Sakai, “Direct Interaction Between Carcinoma Cells and Cancer Associated Fibroblasts for the Regulation of Cancer Invasion,” Cancers (Basel) 7, no. 4 (2015): 2054–2062.

[419] P. Zhang, C. Zhang, X. Li, et al., “Immunotherapy for Gastric Cancer: Advances and Challenges,” MedComm–Oncology 3, no. 4 (2024): e92.

[420] D. Hanahan and M. Coussens Lisa, “Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment,” Cancer Cell 21, no. 3 (2012): 309–322.

[421] A. Ray and P. Cleary Margot, “The Potential Role of Leptin in Tumor Invasion and Metastasis,” Cytokine & Growth Factor Reviews 38 (2017): 80–97.

[422] E. Sounni Nor and A. Noel, “Targeting the Tumor Microenvironment for Cancer Therapy,” Clinical Chemistry 59, no. 1 (2013): 85–93.

[423] S. Jaillon, A. Ponzetta, D. Di Mitri, et al., “Neutrophil Diversity and Plasticity in Tumour Progression and Therapy,” Nature Reviews Cancer 20, no. 9 (2020): 485–503.

[424] B. Eruslanov Evgeniy, “Phenotype and Function of Tumor-Associated Neutrophils and Their Subsets in Early-Stage Human Lung Cancer,” Cancer Immunology, Immunotherapy 66, no. 8 (2017): 997–1006.

[425] E. Shaul Merav and Z. G. Fridlender, “Cancer-Related Circulating and Tumor-Associated Neutrophils–Subtypes, Sources and Function,” The FEBS journal 285 (2018): 4316–4342.

[426] M. A. Giese, L. E. Hind, and A. Huttenlocher, “Neutrophil Plasticity in the Tumor Microenvironment,” The Journal of the American Society of Hematology 133, no. 20 (2019): 2159–2167.

[427] W. Treffers Louise, H. Hiemstra Ida, T. W. Kuijpers, et al., “Neutrophils in Cancer,” Immunological Reviews 273, no. 1 (2016): 312–328.

[428] Y. Zhang, L. Guoqiang, M. Sun, et al., “Targeting and Exploitation of Tumor-Associated Neutrophils to Enhance Immunotherapy and Drug Delivery for Cancer Treatment,” Cancer Biology & Medicine 17, no. 1 (2020): 32–43.

[429] E. Shaul Merav and Z. G. Fridlender, “Tumour-Associated Neutrophils in Patients With Cancer,” Nature Reviews Clinical oncology 16, no. 10 (2019): 601–620.

[430] A. Ocana, C. Nieto-Jiménez, A. Pandiella, et al., “Neutrophils in Cancer: Prognostic Role and Therapeutic Strategies,” Molecular Cancer 16 (2017): 1–7.

[431] W. Liu, W. Wang, X. Wang, et al., “Cisplatin-Stimulated Macrophages Promote Ovarian Cancer Migration via the Ccl20-Ccr6 Axis,” Cancer Letters 472 (2020): 59–69.

[432] C. W. Wanderley, D. F. Colon, M. Luiz Joao Paulo, et al., “Paclitaxel Reduces Tumor Growth by Reprogramming Tumor-Associated Macrophages to an M1 Profile in a Tlr4-Dependent Manner,” Cancer Research 78 (2018): 5891–5900.

[433] Y. Li, Z. Shen, Z. Chai, et al., “Targeting Ms4a4a on Tumour-Associated Macrophages Restores Cd8+ T-Cell-Mediated Antitumour Immunity,” Gut 72, no. 12 (2023): 2307–2320.

[434] C. Salvagno, M. Ciampricotti, S. Tuit, et al., “Therapeutic Targeting of Macrophages Enhances Chemotherapy Efficacy by Unleashing Type I Interferon Response,” Nature Cell Biology 21, no. 4 (2019): 511–521.

[435] D. Wolff, C. Cutler, S. J. Lee, et al., “Axatilimab in Recurrent or Refractory Chronic Graft-Versus-Host Disease,” New England Journal of Medicine 391 (2024): 1002–1014.

[436] S. Song, H. Xia, M. Guo, et al., “Role of Macrophage in Nanomedicine-Based Disease Treatment,” Drug Delivery 28, no. 1 (2021): 752–766.

[437] A. L. Facklam, L. R. Volpatti, and D. G. Anderson, “Biomaterials for Personalized Cell Therapy,” Advanced Materials 32, no. 13 (2020): e1902005.

[438] A. B. Kuznetsova, E. P. Kolesova, A. Parodi, et al., “Reprogramming Tumor-Associated Macrophage Using Nanocarriers: New Perspectives to Halt Cancer Progression,” Pharmaceutics 16, no. 5 (2024), https://doi.org/10.3390/pharmaceutics16050636.

[439] R. Sumitomo, T. Hirai, M. Fujita, et al., “Pd-L1 Expression on Tumor-Infiltrating Immune Cells Is Highly Associated With M2 Tam and Aggressive Malignant Potential in Patients With Resected Non-Small Cell Lung Cancer,” Lung Cancer 136 (2019): 136–144.

[440] Y. Yin, B. Liu, Y. Cao, et al., “Colorectal Cancer-Derived Small Extracellular Vesicles Promote Tumor Immune Evasion by Upregulating Pd-L1 Expression in Tumor-Associated Macrophages,” Advanced Science 9, no. 9 (2022): 2102620.

[441] P. Hartley Genevieve, C. Lyndah, T. Ammons Dylan, et al., “Programmed Cell Death Ligand 1 (Pd-L1) Signaling Regulates Macrophage Proliferation and Activation,” Cancer Immunology Research 6, no. 10 (2018): 1260–1273.

[442] Z. Zhang, X. Liu, D. Chen, et al., “Radiotherapy Combined With Immunotherapy: The Dawn of Cancer Treatment,” Signal Transduct Target Ther 7, no. 1 (2022): 258.

[443] R. A. Mcmahon, C. D'souza, P. J. Neeson, et al., “Innate Immunity: Looking beyond T-Cells in Radiation and Immunotherapy Combinations,” Neoplasia 46 (2023): 100940.

[444] , “Correction: Short-Course Radiotherapy Promotes Pro-Inflammatory Macrophages via Extracellular Vesicles in Human Rectal Cancer.” Journal for ImmunoTherapy of Cancer 8, no. 2 (2020), https://doi.org/10.1136/jitc-2020-000667corr1.

[445] R. Evans and P. Alexander, “Role of Macrophages in Tumour Immunity: I. Co-Operation Between Macrophages and Lymphoid Cells in Syngeneic Tumour Immunity,” Immunology 23, no. 4 (1972): 615.

[446] L. Milas, J. Wike, N. Hunter, et al., “Macrophage Content of Murine Sarcomas and Carcinomas: Associations With Tumor Growth Parameters and Tumor Radiocurability,” Cancer Research 47, no. 4 (1987): 1069–1075.

[447] M. J. Buiting Antoinette and V. Rooijen Nico, “Liposome Mediated Depletion of Macrophages: An Approach for Fundamental Studies,” Journal of Drug Targeting 2, no. 5 (1994): 357–362.

[448] J. Rogers Michael, S. Gordon, H. L. Benford, et al., “Cellular and Molecular Mechanisms of Action of Bisphosphonates,” Cancer: Interdisciplinary International Journal of the American Cancer Society 88, no. S12 (2000): 2961–2978.

[449] J. R. Ross, Y. Saunders, P. M. Edmonds, et al., “A Systematic Review of the Role of Bisphosphonates in Metastatic Disease,” Health Technology Assessment (Winchester, England) 8, no. 4 (2004). III-.

[450] S. M. Zeisberger, B. Odermatt, C. Marty, et al., “Clodronate-Liposome-Mediated Depletion of Tumour-Associated Macrophages: A New and Highly Effective Antiangiogenic Therapy Approach,” British Journal of Cancer 95, no. 3 (2006): 272–281.

[451] E. Giraudo, M. Inoue, and D. Hanahan, “An Amino-Bisphosphonate Targets Mmp-9–Expressing Macrophages and Angiogenesis to Impair Cervical Carcinogenesis,” The Journal of Clinical Investigation 114, no. 5 (2004): 623–633.

[452] P. Seiler, P. Aichele, B. Odermatt, et al., “Crucial Role of Marginal Zone Macrophages and Marginal Zone Metallophils in the Clearance of Lymphocytic Choriomeningitis Virus Infection,” European Journal of Immunology 27, no. 10 (1997): 2626–2633.

[453] W. Tyner Jeffrey, O. Uchida, N. Kajiwara, et al., “Ccl5-Ccr5 Interaction Provides Antiapoptotic Signals for Macrophage Survival during Viral Infection,” Nature Medicine 11, no. 11 (2005): 1180–1187.

[454] K. Mulder, A. A. Patel, T. Kong Wan, et al., “Cross-Tissue Single-Cell Landscape of Human Monocytes and Macrophages in Health and Disease,” Immunity 54, no. 8 (2021): 1883–1900. e5.

[455] M. Nahrendorf and F. K. Swirski, “Abandoning M1/M2 for a Network Model of Macrophage Function,” Circulation Research 119, no. 3 (2016): 414–417.

[456] D. M. Mosser and J. P. Edwards, “Exploring the Full Spectrum of Macrophage Activation,” Nature Reviews Immunology 8, no. 12 (2008): 958–969.

[457] A. Giladi, F. Paul, Y. Herzog, et al., “Single-Cell Characterization of Haematopoietic Progenitors and Their Trajectories in Homeostasis and Perturbed Haematopoiesis,” Nature Cell Biology 20, no. 7 (2018): 836–846.

[458] D. A. Lawson, K. Kessenbrock, R. T. Davis, et al., “Tumour Heterogeneity and Metastasis at Single-Cell Resolution,” Nature Cell Biology 20, no. 12 (2018): 1349–1360.

[459] X. Ren, L. Zhang, Y. Zhang, et al., “Insights Gained From Single-Cell Analysis of Immune Cells in the Tumor Microenvironment,” Annual Review of Immunology 39, no. 1 (2021): 583–609.

[460] M. A. Ruo-Yu, B. Annabel, and Q. Bin-Zhi, “Macrophage Diversity in Cancer Revisited in the Era of Single-Cell Omics,” Trends in Immunology 43, no. 7 (2022): 546–563.

[461] C. A. Gomez-Roca, P. A. Cassier, A. Italiano, et al., “Phase I Study of Rg7155, a Novel Anti-Csf1r Antibody, in Patients With Advanced/Metastatic Solid Tumors,” American Society of Clinical Oncology (2015).

[462] Y. Zhu, L. Knolhoff Brett, 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, no. 18 (2014): 5057–5069.

[463] Y. Yang, H. E. Wu, Y. Yang, et al., “Dual Blockade of Cd47 and Cd24 Signaling Using a Novel Bispecific Antibody Fusion Protein Enhances Macrophage Immunotherapy,” Molecular Therapy-Oncolytics 31 (2023): 100747.

[464] H. June Carl, S. O'connor Roddy, U. Kawalekar Omkar, et al., “Car T Cell Immunotherapy for Human Cancer,” Science 359, no. 6382 (2018): 1361–1365.

[465] L. Beatty Gregory, R. Haas Andrew, V. Maus Marcela, et al., “Mesothelin-Specific Chimeric Antigen Receptor Mrna-Engineered T Cells Induce Antitumor Activity in Solid Malignancies,” Cancer Immunology Research 2, no. 2 (2014): 112–120.

[466] D. Marin, Y. E. Li, R. Basar, et al., “Safety, Efficacy and Determinants of Response of Allogeneic Cd19-Specific Car-Nk Cells in Cd19+ B Cell Tumors: A Phase 1/2 Trial,” Nature Medicine 30, no. 3 (2024): 772–784.

[467] R. H. Andrew, L. Tanyi Janos, H. O'hara Mark, et al., “Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers,” Molecular Therapy 27, no. 11 (2019): 1919–1929.

[468] H. Yu, E. Sotillo, C. Harrington, et al., “Repeated Loss of Target Surface Antigen After Immunotherapy in Primary Mediastinal Large B Cell Lymphoma,” American Journal of Hematology 92, no. 1 (2016): E11.

[469] M. O'rourke Donald, P. Nasrallah MacLean, A. Desai, et al., “A Single Dose of Peripherally Infused Egfrviii-Directed Car T Cells Mediates Antigen Loss and Induces Adaptive Resistance in Patients With Recurrent Glioblastoma,” Science Translational Medicine 9, no. 399 (2017): eaaa0984.

[470] M. Poorebrahim, J. Melief, Y. Pico De Coaña, et al., “Counteracting Car T Cell Dysfunction,” Oncogene 40, no. 2 (2021): 421–435.

[471] A. Reiss Kim, G. Angelos Mathew, and E. C. Dees, “Car-Macrophage Therapy for Her2-Overexpressing Advanced Solid Tumors: A Phase 1 Trial,” Nature Medicine (2025): 1–12.

[472] W. Ma and C. Jamieson, “Chimeric Antigen Receptor-Macrophage Therapy Enters the Clinic: The First-in-Human Trial for Her2(+) Solid Tumors,” MedComm 6, no. 9 (2025): e70374.

[473] Y. Chen, Z. Yu, X. Tan, et al., “Car-Macrophage: A New Immunotherapy Candidate Against Solid Tumors,” Biomedicine & Pharmacotherapy 139 (2021): 111605.

[474] A. Wróblewska, A. Szczygieł, B. O. Szermer-Olearnik, et al., “Macrophages as Promising Carriers for Nanoparticle Delivery in Anticancer Therapy,” International Journal of Nanomedicine (2023): 4521–4539.

[475] D. Mayya Alexandrovna, T. Sergey Yurjevich, R. Vladimir Alexandrovich, et al., “Boron Neutron Capture Therapy: Current Status and Future Perspectives,” Cancer communications 40, no. 9 (2020): 406–421.

[476] H. Cao, Z. Dan, X. He, et al., “Liposomes Coated With Isolated Macrophage Membrane Can Target Lung Metastasis of Breast Cancer,” ACS Nano 10, no. 8 (2016): 7738–7748.

[477] K. Kuerban, X. Gao, H. Zhang, et al., “Doxorubicin-Loaded Bacterial Outer-Membrane Vesicles Exert Enhanced Anti-Tumor Efficacy in Non-Small-Cell Lung Cancer,” Acta pharmaceutica Sinica B 10, no. 8 (2020): 1534–1548.

[478] J. Fu, D. Wang, D. Mei, et al., “Macrophage Mediated Biomimetic Delivery System for the Treatment of Lung Metastasis of Breast Cancer,” Journal of Controlled Release 204 (2015): 11–19.

[479] R. Kalluri and V. S. Lebleu, “The Biology, Function, and Biomedical Applications of Exosomes,” Science 367, no. 6478 (2020), https://doi.org/10.1126/science.aau6977.

[480] T. Wu, Y. Liu, Y. Cao, et al., “Engineering Macrophage Exosome Disguised Biodegradable Nanoplatform for Enhanced Sonodynamic Therapy of Glioblastoma,” Advanced Materials 34, no. 15 (2022): e2110364.

[481] S. Rayamajhi, T. D. T. Nguyen, R. Marasini, et al., “Macrophage-Derived Exosome-Mimetic Hybrid Vesicles for Tumor Targeted Drug Delivery,” Acta Biomaterialia 94 (2019): 482–494.

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