Improvement of the Anticancer Efficacy of PD-1/PD-L1 Blockade: Advances in Molecular Mechanisms and Therapeutic Strategies

Abstract

The clinical success of PD-1/PD-L1 blockade has revolutionized cancer immunotherapy. However, the issues of immune resistance have become increasingly prominent, representing a critical limitation in modern oncology. This phenomenon has prompted efforts to elucidate the mechanisms underlying both types of resistance and to find breakthrough therapeutic strategies. This article provides a comprehensive overview of PD-1/PD-L1 blockade resistance mechanisms from both primary and acquired resistance perspectives, including tumor intrinsic factors, immune microenvironment components, and systemic factors. Building on this foundation, emerging research demonstrates that type I interferons (IFNs), particularly IFN-α and IFN-β, play crucial immunomodulatory roles in overcoming resistance to PD-1/PD-L1 blockade. We delineate six molecular mechanisms through which IFN-α/β enhance PD-1/PD-L1 blockade efficacy, and innovative strategies are proposed to therapeutically boost IFN-α/β production, including gene editing techniques, targeting the cGAS-STING or TLR pathway and so on. Furthermore, insights into current challenges and future directions of the application of IFN-α/β to improve PD-1/PD-L1 blockade are discussed. This review holds significant academic value by not only synthesizing current knowledge on PD-1/PD-L1 resistance mechanisms but also pioneering a framework for leveraging type I IFNs to overcome these barriers.

Keywords

PD-1/PD-L1 blockade resistance / cancer treatment / type I interferons / cGAS-STING pathway

References

[1] J. Larkin, V. Chiarion-Sileni, R. Gonzalez, et al., “Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma,” New England Journal of Medicine 373, no. 1 (2015): 23-34.

[2] F. G. Dall'Olio, A. Marabelle, C. Caramella, et al., “Tumour Burden and Efficacy of Immune-checkpoint Inhibitors,” Nature Reviews Clinical Oncology 19, no. 2 (2022): 75-90.

[3] 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.

[4] H. Dong, G. Zhu, K. Tamada, et al., “B7-H1, a Third Member of the B7 Family, Co-stimulates T-cell Proliferation and Interleukin-10 Secretion,” Nature Medicine 5, no. 12 (1999): 1365-1369.

[5] S. L. Topalian, F. S. Hodi, J. R. Brahmer, et al., “Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer,” New England Journal of Medicine 366, no. 26 (2012): 2443-2454.

[6] C. Robert, A. Ribas, J. D. Wolchok, et al., “Anti-programmed-death-receptor-1 Treatment with Pembrolizumab in Ipilimumab-Refractory Advanced Melanoma: A Randomised Dose-Comparison Cohort of a Phase 1 Trial,” Lancet 384, no. 9948 (2014): 1109-1117.

[7] L. Chen and X. Han, “Anti-PD-1/PD-L1 Therapy of human Cancer: Past, Present, and Future,” Journal of Clinical Investigation 125, no. 9 (2015): 3384-3391.

[8] J. Yu, Y. Xiang, Y. Gao, et al., “PKCα Inhibitors Promote Breast Cancer Immune Evasion by Maintaining PD-L1 Stability,” Acta Pharmaceutica Sinica B 14, no. 10 (2024): 4378-4395.

[9] Z. Dai, J. Chen, and Y. Wang, “Effect of PD-1/PD-L1 Immune Checkpoint Inhibitor in Squamous and Nonsquamous Non-small Cell Lung Cancer: A Systematic Review and Meta-Analysis,” Malignancy Spectrum 1, no. 3 (2024): 197-204.

[10] M. D. Vesely, T. Zhang, and L. Chen, “Resistance Mechanisms to Anti-PD Cancer Immunotherapy,” Annual Review of Immunology 40 (2022): 45-74.

[11] S. L. Topalian, J. M. Taube, and D. M. Pardoll, “Neoadjuvant Checkpoint Blockade for Cancer Immunotherapy,” Science 367, no. 6477 (2020): eaax0182.

[12] J. M. Zaretsky, A. Garcia-Diaz, D. S. Shin, et al., “Mutations Associated With Acquired Resistance to PD-1 Blockade in Melanoma,” New England Journal of Medicine 375, no. 9 (2016): 819-829.

[13] M. C. Andrews and J. A. Wargo, “Immunotherapy Resistance: The Answers Lie Ahead—Not in Front—of Us,” Journal for ImmunoTherapy of Cancer 5 (2017): 1-3.

[14] R. S. Herbst, J.-C. Soria, M. Kowanetz, et al., “Predictive Correlates of Response to the Anti-PD-L1 Antibody MPDL3280A in Cancer Patients,” Nature 515, no. 7528 (2014): 563-567.

[15] M. Yu, Z. Peng, M. Qin, et al., “Interferon-γ Induces Tumor Resistance to Anti-PD-1 Immunotherapy by Promoting YAP Phase Separation,” Molecular Cell 81, no. 6 (2021): 1216-1230.

[16] D. S. Shin, J. M. Zaretsky, H. Escuin-Ordinas, et al., “Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations,” Cancer discovery 7, no. 2 (2017): 188-201.

[17] J. X. Caushi, J. Zhang, Z. Ji, et al., “Transcriptional Programs of Neoantigen-Specific TIL in Anti-PD-1-Treated Lung Cancers,” Nature 596, no. 7870 (2021): 126-132.

[18] H. Long, Q. Jia, L. Wang, et al., “Tumor-induced Erythroid Precursor-differentiated Myeloid Cells Mediate Immunosuppression and Curtail Anti-PD-1/PD-L1 Treatment Efficacy,” Cancer Cell 40, no. 6 (2022): 674-693.

[19] B. Routy, J. G. Lenehan, W. H. Miller, et al., “Fecal Microbiota Transplantation plus Anti-PD-1 Immunotherapy in Advanced Melanoma: A Phase I Trial,” Nature Medicine 29, no. 8 (2023): 2121-2132.

[20] C. Guo, L. Lin, Y. Wang, et al., “Nano Drug Delivery Systems for Advanced Immune Checkpoint Blockade Therapy,” Theranostics 15, no. 11 (2025): 5440-5480.

[21] T. He, M. Hu, S. Zhu, et al., “A Tactical Nanomissile Mobilizing Antitumor Immunity Enables Neoadjuvant Chemo-immunotherapy to Minimize Postsurgical Tumor Metastasis and Recurrence,” Acta Pharmaceutica Sinica B 13, no. 2 (2023): 804-818.

[22] L. Luo, F. Xu, H. Peng, et al., “Stimuli-Responsive Polymeric Prodrug-Based Nanomedicine Delivering Nifuroxazide and Doxorubicin Against Primary Breast Cancer and Pulmonary Metastasis,” Journal of Control Release 318 (2020): 124-135.

[23] K. M. Campbell, M. Amouzgar, S. M. Pfeiffer, et al., “Prior Anti-CTLA-4 Therapy Impacts Molecular Characteristics Associated With anti-PD-1 Response in Advanced Melanoma,” Cancer Cell 41, no. 4 (2023): 791-806.

[24] M. Wu, Q. Huang, Y. Xie, et al., “Improvement of the Anticancer Efficacy of PD-1/PD-L1 Blockade via Combination Therapy and PD-L1 Regulation,” Journal of Hematology & Oncology 15, no. 1 (2022): 24.

[25] Y. Y. Janjigian, K. Shitara, M. Moehler, et al., “First-Line Nivolumab Plus Chemotherapy versus Chemotherapy Alone for Advanced Gastric, Gastro-oesophageal Junction, and Oesophageal Adenocarcinoma (CheckMate 649): A Randomised, Open-label, Phase 3 Trial,” Lancet 398, no. 10294 (2021): 27-40.

[26] H. Li, Q. Gong, and K. Luo, “Biomarker-driven Molecular Imaging Probes in Radiotherapy,” Theranostics 14, no. 10 (2024): 4127-4146.

[27] J. Wu, X. Zhao, Q. Sun, et al., “Synergic Effect of PD-1 Blockade and Endostar on the PI3K/AKT/mTOR-Mediated Autophagy and Angiogenesis in Lewis lung Carcinoma Mouse Model,” Biomedicine & Pharmacotherapy 125 (2020): 109746.

[28] E. Sugiyama, Y. Togashi, Y. Takeuchi, et al., “Blockade of EGFR Improves Responsiveness to PD-1 Blockade in EGFR-mutated Non-Small Cell Lung Cancer,” Science Immunology 5, no. 43 (2020): eaav3937.

[29] A. Ribas, R. Dummer, I. Puzanov, et al., “Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy,” Cell 170, no. 6 (2017): 1109-1119.

[30] R. Grosser, L. Cherkassky, N. Chintala, et al., “Combination Immunotherapy With CAR T Cells and Checkpoint Blockade for the Treatment of Solid Tumors,” Cancer Cell 36, no. 5 (2019): 471-482.

[31] Y. Zheng, S. Luo, M. Xu, et al., “Transepithelial Transport of Nanoparticles in Oral Drug Delivery: From the Perspective of Surface and Holistic Property Modulation,” Acta Pharmaceutica Sinica B 14, no. 9 (2024): 3876-3900.

[32] H. Zhang, L. Liu, J. Liu, et al., “Roles of Tumor-associated Macrophages in Anti-PD-1/PD-L1 Immunotherapy for Solid Cancers,” Molecular cancer 22, no. 1 (2023): 58.

[33] L. Pei, Y. Liu, L. Liu, et al., “Roles of Cancer-Associated Fibroblasts (CAFs) in Anti- PD-1/PD-L1 Immunotherapy for Solid Cancers,” Molecular cancer 22, no. 1 (2023): 29.

[34] L. Qin, J. Cao, K. Shao, et al., “A Tumor-to-Lymph Procedure Navigated Versatile Gel System for Combinatorial Therapy Against Tumor Recurrence and Metastasis,” Science Advances 6, no. 36 (2020): eabb3116.

[35] L. Bod, Y.-C. Kye, J. Shi, et al., “B-Cell-Specific Checkpoint Molecules That Regulate Anti-Tumour Immunity,” Nature 619, no. 7969 (2023): 348-356.

[36] J. D. Klement, P. S. Redd, C. Lu, et al., “Tumor PD-L1 Engages Myeloid PD-1 to Suppress Type I Interferon to Impair Cytotoxic T Lymphocyte Recruitment,” Cancer Cell 41, no. 3 (2023): 620-636.

[37] M. B. Fuertes, S.-R. Woo, B. Burnett, et al., “Type I Interferon Response and Innate Immune Sensing of Cancer,” Trends in Immunology 34, no. 2 (2013): 67-73.

[38] S. Pestka, C. D. Krause, and M. R. Walter, “Interferons, Interferon-Like Cytokines, and Their Receptors,” Immunological Reviews 202 (2004): 8-32.

[39] Z. Qi, Z. Xu, L. Zhang, et al., “Overcoming Resistance to Immune Checkpoint Therapy in PTEN-Null Prostate Cancer by Intermittent Anti-PI3Kα/β/δ Treatment,” Nature Communications 13, no. 1 (2022): 182.

[40] Y. Liang, H. Tang, J. Guo, et al., “Targeting IFNα to Tumor by Anti-PD-L1 Creates Feedforward Antitumor Responses to Overcome Checkpoint Blockade Resistance,” Nature Communications 9, no. 1 (2018): 4586.

[41] J. Liu, X. Li, Y. Li, et al., “Metformin-based Nanomedicines for Reprogramming Tumor Immune Microenvironment,” Theranostics 15, no. 3 (2025): 993-1016.

[42] H. Li, Y. Zeng, H. Zhang, et al., “Functional Gadolinium-based Nanoscale Systems for Cancer Theranostics,” Journal of Control Release 329 (2021): 482-512.

[43] L. Bai, J. Yang, S. Yu, et al., “Self-Sufficient Nanoparticles with Dual-enzyme Activity Trigger Radical Storms and Activate Cascade-amplified Antitumor Immunologic Responses,” Acta Pharmaceutica Sinica B 14, no. 2 (2024): 821-835.

[44] R. Bao, A. Hutson, A. Madabhushi, et al., “Ten Challenges and Opportunities in Computational Immuno-oncology,” Journal for ImmunoTherapy of Cancer 12, no. 10 (2024): e009721.

[45] M. Arafat Hossain, “A Comprehensive Review of Immune Checkpoint Inhibitors for Cancer Treatment,” International Immunopharmacology 143, no. Pt 2 (2024): 113365.

[46] J. Liu, Y. Bai, Y. Li, et al., “Reprogramming the Immunosuppressive Tumor Microenvironment Through Nanomedicine: An Immunometabolism Perspective,” EBioMedicine 107 (2024): 105301.

[47] T. Wang, W. Ma, Z. Zou, et al., “PD-1 Blockade Treatment in Melanoma: Mechanism of Response and Tumor-Intrinsic Resistance,” Cancer Science 116, no. 2 (2025): 329-337. 2024.

[48] G. R. Khosravi, S. Mostafavi, S. Bastan, N. Ebrahimi, R. S. Gharibvand, and N. Eskandari, “Immunologic Tumor Microenvironment Modulators for Turning Cold Tumors Hot,” Cancer Communications (Lond) 44, no. 5 (2024): 521-553.

[49] S. Jhunjhunwala, C. Hammer, and L. Delamarre, “Antigen Presentation in Cancer: Insights Into Tumour Immunogenicity and Immune Evasion,” Nature Reviews Cancer 21, no. 5 (2021): 298-312.

[50] F. Baharom, R. A. Ramirez-Valdez, A. Khalilnezhad, et al., “Systemic Vaccination Induces CD8+ T Cells and Remodels the Tumor Microenvironment,” Cell 185, no. 23 (2022): 4317-4332.e15.

[51] X. Wang, G. Lamberti, A. Di Federico, et al., “Tumor Mutational Burden for the Prediction of PD-(L)1 Blockade Efficacy in Cancer: Challenges and Opportunities,” Annals of Oncology 35, no. 6 (2024): 508-522.

[52] D. L. Jardim, A. Goodman, M. de, et al., “The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker,” Cancer Cell 39, no. 2 (2021): 154-173.

[53] D. Chen, X. Ling, Y. Wang, et al., “Autophagy-activating Aluminum Hydroxide Nanovaccine for Enhanced Antigen Presentation and Anti-Tumor Immunity,” Journal of Control Release 377 (2025): 223-235.

[54] V. Subbiah, M. A. Gouda, B. Ryll, et al., “The Evolving Landscape of Tissue-Agnostic Therapies in Precision Oncology,” CA: A Cancer Journal for Clinicians 74, no. 5 (2024): 433-452.

[55] S. Naskar, N. Sriraman, A. Sarkar, et al., “Tumor Antigen Presentation and the Associated Signal Transduction During Carcinogenesis,” Pathology, Research and Practice 261 (2024): 155485.

[56] R. R. Brutkiewicz, “Cell Signaling Pathways That Regulate Antigen Presentation,” Journal of Immunology 197, no. 8 (2016): 2971-2979.

[57] W. Shi, N. Liu, and H. Lu, “Advancements and Challenges in Immunocytokines: A New Arsenal Against Cancer,” Acta Pharmaceutica Sinica B 14, no. 11 (2024): 4649-4664.

[58] K. K. W. To and W. C. Cho, “Drug Repurposing to Circumvent Immune Checkpoint Inhibitor Resistance in Cancer Immunotherapy,” Pharmaceutics 15, no. 8 (2023): 2166.

[59] Y.-R. Lee, M. Chen, and P. P. Pandolfi, “The Functions and Regulation of the PTEN Tumour Suppressor: New Modes and Prospects,” Nature Reviews Molecular Cell Biology 19, no. 9 (2018): 547-562.

[60] W. Peng, J. Q. Chen, C. Liu, et al., “Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy,” Cancer Discov 6, no. 2 (2016): 202-216.

[61] V. S. Schäfer, P. Brossart, K. J. Warrington, et al., “The Role of Autoimmunity and Autoinflammation in Giant Cell Arteritis: A Systematic Literature Review,” Autoimmunity Reviews 22, no. 6 (2023): 103328.

[62] S. Subhadarshini, S. Sahoo, S. Debnath, et al., “Dynamical Modeling of Proliferative-Invasive Plasticity and IFNγ Signaling in Melanoma Reveals Mechanisms of PD-L1 Expression Heterogeneity,” Journal for ImmunoTherapy of Cancer 11, no. 9 (2023): e006766.

[63] J. Han, M. Wu, and Z. Liu, “Dysregulation in IFN-γ Signaling and Response: The Barricade to Tumor Immunotherapy,” Frontiers in Immunology 14 (2023): 1190333.

[64] J. L. Benci, B. Xu, Y. Qiu, et al., “Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade,” Cell 167, no. 6 (2016): 1540-1554.e12.

[65] J. Yang, L. Song, M. Shen, et al., “Hierarchically Responsive Tumor-Microenvironment-Activated Nano-Artificial Virus for Precise Exogenous and Endogenous Apoptosis Coactivation,” Advanced Functional Materials 31, no. 37 (2021): 2104423.

[66] G. Shi, Y. Cui, J. Zhao, et al., “Identifying TOPK and Hypoxia Hallmarks in Esophageal Tumors for Photodynamic/Chemo/Immunotherapy and Liver Metastasis Inhibition With Nanocarriers,” ACS Nano 17, no. 7 (2023): 6193-6207.

[67] Y. Xu, J. Xiong, X. Sun, et al., “Targeted Nanomedicines Remodeling Immunosuppressive Tumor Microenvironment for Enhanced Cancer Immunotherapy,” Acta Pharmaceutica Sinica B 12, no. 12 (2022): 4327-4347.

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

[69] C. Tay, A. Tanaka, and S. Sakaguchi, “Tumor-Infiltrating Regulatory T Cells as Targets of Cancer Immunotherapy,” Cancer Cell 41, no. 3 (2023): 450-465.

[70] K. Ratajczak, H. Grel, P. Olejnik, et al., “Current Progress, Strategy, and Prospects of PD-1/PDL-1 Immune Checkpoint Biosensing Platforms for Cancer Diagnostics, Therapy Monitoring, and Drug Screening,” Biosensors & Bioelectronics 240 (2023): 115644.

[71] M. A. Ortega, D. L. Boaru, D. De Leon-Oliva, et al., “PD-1/PD-L1 Axis: Implications in Immune Regulation, Cancer Progression, and Translational Applications,” Journal of Molecular Medicine (Berl) 102, no. 8 (2024): 987-1000.

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

[73] Y. Li, Z. Duan, D. Pan, et al., “Attenuating Metabolic Competition of Tumor Cells for Favoring the Nutritional Demand of Immune Cells by a Branched Polymeric Drug Delivery System,” Advanced Materials 35, no. 11 (2023): 2210161.

[74] M. Zhang, L. Huang, G. Ding, et al., “Interferon Gamma Inhibits CXCL8-CXCR2 Axis Mediated Tumor-Associated Macrophages Tumor Trafficking and Enhances Anti-PD1 Efficacy in Pancreatic Cancer,” Journal for ImmunoTherapy of Cancer 8, no. 1 (2020): e000308.

[75] S. L. Highfill, Y. Cui, A. J. Giles, et al., “Disruption of CXCR2-mediated MDSC Tumor Trafficking Enhances Anti-PD1 Efficacy,” Science Translational Medicine 6, no. 237 (2014): 237ra267.

[76] S. M. Ansell, A. M. Lesokhin, I. Borrello, et al., “PD-1 Blockade With nivolumab in Relapsed or Refractory Hodgkin's Lymphoma,” New England Journal of Medicine 372, no. 4 (2015): 311-319.

[77] P. Sharma, S. Hu-Lieskovan, J. A. Wargo, et al., “Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy,” Cell 168, no. 4 (2017): 707-723.

[78] D. Memon, A. J. Schoenfeld, D. Ye, et al., “Clinical and Molecular Features of Acquired Resistance to Immunotherapy in Non-Small Cell Lung Cancer,” Cancer Cell 42, no. 2 (2024): 209-224.e9.

[79] S. M. Hossain, G. Gimenez, P. A. Stockwell, et al., “Innate Immune Checkpoint Inhibitor Resistance Is Associated With Melanoma Sub-types Exhibiting Invasive and De-differentiated Gene Expression Signatures,” Frontiers in Immunology 13 (2022): 955063.

[80] H. N. Bell and W. Zou, “Beyond the Barrier: Unraveling the Mechanisms of Immunotherapy Resistance,” Annual Review of Immunology 42, no. 1 (2024): 521-550.

[81] S. Bagchi, R. Yuan, and E. G. Engleman, “Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance,” Annual Review of Pathology 16 (2021): 223-249.

[82] S. Koyama, E. A. Akbay, Y. Y. Li, et al., “Adaptive Resistance to Therapeutic PD-1 Blockade Is Associated With Upregulation of Alternative Immune Checkpoints,” Nature Communications 7 (2016): 10501.

[83] B. Zhang, J. Liu, Y. Mo, et al., “CD8+ T Cell Exhaustion and Its Regulatory Mechanisms in the Tumor Microenvironment: Key to the Success of Immunotherapy,” Frontiers in Immunology 15 (2024): 1476904.

[84] K. Kang, X. Lin, P. Chen, et al., “T Cell Exhaustion in human Cancers,” Biochimica et Biophysica Acta - Reviews on Cancer 1879, no. 5 (2024): 189162.

[85] Q. Wang, Q. Yang, and X. Liu, “The Microbiota-gut-brain Axis and Neurodevelopmental Disorders,” Protein Cell 14, no. 10 (2023): 762-775.

[86] X. Kang, H. C.-H. Lau, and J. Yu, “Modulating Gut Microbiome in Cancer Immunotherapy: Harnessing Microbes to Enhance Treatment Efficacy,” Cell Reports Medicine 5, no. 4 (2024): 101478.

[87] Y. Xie and F. Liu, “The Role of the Gut Microbiota in Tumor, Immunity, and Immunotherapy,” Frontiers in Immunology 15 (2024): 1410928.

[88] Z. Zhu, S. Cao, H. Li, et al., “Myeloid-Derived Suppressor Cell-Targeted Virus-Like Particles Synergistically Activate Innate Immune Response for Cancer Immunotherapy,” Journal of Control Release 381 (2025): 113603.

[89] B. Routy, E. Le Chatelier, L. Derosa, et al., “Gut Microbiome Influences Efficacy of PD-1-Based Immunotherapy Against Epithelial Tumors,” Science 359, no. 6371 (2018): 91-97.

[90] R. Zhu, T. Lang, W. Yan, et al., “Gut Microbiota: Influence on Carcinogenesis and Modulation Strategies by Drug Delivery Systems to Improve Cancer Therapy,” Advanced Science (Weinh) 8, no. 10 (2021): 2003542.

[91] V. Gopalakrishnan, C. N. Spencer, L. Nezi, et al., “Gut Microbiome Modulates Response to anti-PD-1 Immunotherapy in Melanoma Patients,” Science 359, no. 6371 (2018): 97-103.

[92] Y. Li, F. Tong, Y. Wang, et al., “In Situ Tumor Vaccine With Optimized Nanoadjuvants and Lymph Node Targeting Capacity to Treat Ovarian Cancer and Metastases,” Acta Pharmaceutica Sinica B 14, no. 9 (2024): 4102-4117.

[93] N. Wang, C. Liu, Y. Li, et al., “A Cooperative Nano-CRISPR Scaffold Potentiates Immunotherapy via Activation of Tumour-intrinsic Pyroptosis,” Nature Communications 14, no. 1 (2023): 779.

[94] J. Liu, Y. Cui, H. Cabral, et al., “Glucosylated Nanovaccines for Dendritic Cell-Targeted Antigen Delivery and Amplified Cancer Immunotherapy,” ACS Nano 18, no. 37 (2024): 25826-25840.

[95] F. McNab, K. Mayer-Barber, A. Sher, et al., “Type I Interferons in Infectious Disease,” Nature Reviews Immunology 15, no. 2 (2015): 87-103.

[96] A. Isaacs and J. Lindenmann, “Virus Interference. I. The Interferon,” Proceedings of the Royal Society of London. Series B: Biological Sciences 147, no. 927 (1957): 258-267.

[97] R. M. Roberts, L. Liu, Q. Guo, et al., “The Evolution of the Type I Interferons,” Journal of Interferon & Cytokine Research 18, no. 10 (1998): 805-816.

[98] S. M. O'Carroll, F. D. R. Henkel, and L. A. J. O'Neill, “Metabolic Regulation of Type I Interferon Production,” Immunological Reviews 323, no. 1 (2024): 276-287.

[99] R. Yu, B. Zhu, and D. Chen, “Type I Interferon-mediated Tumor Immunity and Its Role in Immunotherapy,” Cellular and Molecular Life Sciences 79, no. 3 (2022): 191.

[100] L. Zitvogel, L. Galluzzi, O. Kepp, et al., “Type I Interferons in Anticancer Immunity,” Nature Reviews Immunology 15, no. 7 (2015): 405-414.

[101] L. Tiberio, M. Laffranchi, G. Zucchi, et al., “Inhibitory Receptors of Plasmacytoid Dendritic Cells as Possible Targets for Checkpoint Blockade in Cancer,” Frontiers in Immunology 15 (2024): 1360291.

[102] A. C. Hobeika, P. S. Subramaniam, and H. M. Johnson, “IFNalpha Induces the Expression of the Cyclin-dependent Kinase Inhibitor p21 in Human Prostate Cancer Cells,” Oncogene 14, no. 10 (1997): 1165-1170.

[103] H. Kuniyasu, W. Yasui, K. Kitahara, et al., “Growth Inhibitory Effect of Interferon-beta Is Associated with the Induction of Cyclin-Dependent Kinase Inhibitor p27Kip1 in a Human Gastric Carcinoma Cell Line,” Cell Growth & Differentiation 8, no. 1 (1997): 47-52.

[104] M. Matsuoka, K. Tani, and S. Asano, “Interferon-Alpha-Induced G1 Phase Arrest Through Up-regulated Expression of CDK Inhibitors, p19Ink4D and p21Cip1 in Mouse Macrophages,” Oncogene 16, no. 16 (1998): 2075-2086.

[105] N. Tiefenbrun, D. Melamed, N. Levy, et al., “Alpha Interferon Suppresses the Cyclin D3 and cdc25A Genes, Leading to a Reversible G0-Like Arrest,” Molecular and Cellular Biology 16, no. 7 (1996): 3934-3944.

[106] S. Maeda, H. Wada, Y. Naito, et al., “Interferon-α Acts on the S/G2/M Phases to Induce Apoptosis in the G1 Phase of an IFNAR2-expressing Hepatocellular Carcinoma Cell Line,” Journal of Biological Chemistry 289, no. 34 (2014): 23786-23795.

[107] Y. Zhu, X. An, X. Zhang, et al., “STING: A Master Regulator in the Cancer-Immunity Cycle,” Molecular cancer 18, no. 1 (2019): 1-15.

[108] K.-I. Arimoto, S. Miyauchi, T. D. Troutman, et al., “Expansion of Interferon Inducible Gene Pool via USP18 Inhibition Promotes Cancer Cell Pyroptosis,” Nature Communications 14, no. 1 (2023): 251.

[109] N. Yoon, M. S. Park, T. Shigemoto, et al., “Activated human Mesenchymal Stem/Stromal Cells Suppress Metastatic Features of MDA-MB-231 Cells by Secreting IFN-β,” Cell death & disease 7, no. 4 (2016): e2191.

[110] H. Enomoto, L. Tao, R. Eguchi, et al., “The in Vivo Antitumor Effects of Type I-interferon Against Hepatocellular Carcinoma: The Suppression of Tumor Cell Growth and Angiogenesis,” Scientific Reports 7, no. 1 (2017): 12189.

[111] C. P. Dinney, D. R. Bielenberg, P. Perrotte, et al., “Inhibition of Basic Fibroblast Growth Factor Expression, Angiogenesis, and Growth of Human Bladder Carcinoma in Mice by Systemic Interferon-Alpha Administration,” Cancer Research 58, no. 4 (1998): 808-814.

[112] S. F. Huang, S.-J. Kim, A. T. Lee, et al., “Inhibition of Growth and Metastasis of Orthotopic Human Prostate Cancer in Athymic Mice by Combination Therapy With Pegylated Interferon-Alpha-2b and Docetaxel,” Cancer Research 62, no. 20 (2002): 5720-5726.

[113] J. Rautela, N. Baschuk, C. Y. Slaney, et al., “Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer,” Cancer Immunology Research 3, no. 11 (2015): 1207-1217.

[114] S. Forveille, A. Sauvat, S. Zhang, et al., “Assessment of Type I Interferon Responses as a Feature of Immunogenic Cell Death,” Methods in Cell Biology 172 (2022): 135-143.

[115] P. Holicek, E. Guilbaud, V. Klapp, et al., “Type I Interferon and Cancer,” Immunological Reviews 321, no. 1 (2023): 115-127.

[116] R. D. Schreiber, L. J. Old, and M. J. Smyth, “Cancer Immunoediting: Integrating Immunity's Roles in Cancer Suppression and Promotion,” Science 331, no. 6024 (2011): 1565-1570.

[117] J. M. González-Navajas, J. Lee, M. David, et al., “Immunomodulatory Functions of Type I Interferons,” Nature Reviews Immunology 12, no. 2 (2012): 125-135.

[118] Y. Zhu, M. Chen, D. Xu, et al., “The Combination of PD-1 Blockade With Interferon-α Has a Synergistic Effect on Hepatocellular Carcinoma,” Cellular & Molecular Immunology 19, no. 6 (2022): 726-737.

[119] N. Yusuf, S. R. Allie, and B. E. Strauss, “Editorial: Interferons: Key Modulators of the Immune System in Cancer,” Frontiers in Immunology 14 (2023): 1327311.

[120] J. Holzgruber, C. Martins, Z. Kulcsar, et al., “Type I Interferon Signaling Induces Melanoma Cell-Intrinsic PD-1 and Its Inhibition Antagonizes Immune Checkpoint Blockade,” Nature Communications 15, no. 1 (2024): 7165.

[121] Z. Jin, H. Wang, R. Tang, et al., “GATA2 Promotes Castration-Resistant Prostate Cancer Development by Suppressing IFN-β Axis-mediated Antitumor Immunity,” Oncogene 43, no. 34 (2024): 2595-2610.

[122] Y. Zhang, W. Hong, Zheng, et al., “Increased IFN-β Indicates Better Survival in Hepatocellular Carcinoma Treated With Radiotherapy,” Clinical and Experimental Immunology 218, no. 2 (2024): 188-198.

[123] S. Chamani, M. Moossavi, A. Naghizadeh, et al., “Modulatory Properties of Curcumin in Cancer: A Narrative Review on the Role of Interferons,” Phytotherapy Research 37, no. 3 (2023): 1003-1014.

[124] B. Reizis, “Plasmacytoid Dendritic Cells: Development, Regulation, and Function,” Immunity 50, no. 1 (2019): 37-50.

[125] S. Kim, V. Kaiser, E. Beier, et al., “Self-priming Determines High Type I IFN Production by Plasmacytoid Dendritic Cells,” European Journal of Immunology 44, no. 3 (2014): 807-818.

[126] Q. Chen, L. Sun, and Z. J. Chen, “Regulation and Function of the cGAS-STING Pathway of Cytosolic DNA Sensing,” Nature Immunology 17, no. 10 (2016): 1142-1149.

[127] S. L. Ergun, D. Fernandez, T. M. Weiss, et al., “STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition,” Cell 178, no. 2 (2019): 290-301.

[128] G. Shang, C. Zhang, Z. J. Chen, et al., “Cryo-EM Structures of STING Reveal Its Mechanism of Activation by Cyclic GMP-AMP,” Nature 567, no. 7748 (2019): 389-393.

[129] B.-C. Zhang, R. Nandakumar, L. S. Reinert, et al., “STEEP Mediates STING ER Exit and Activation of Signaling,” Nature Immunology 21, no. 8 (2020): 868-879.

[130] G. N. Barber, “STING: Infection, Inflammation and Cancer,” Nature Reviews Immunology 15, no. 12 (2015): 760-770.

[131] Y. Wang, J. Luo, A. Alu, et al., “cGAS-STING Pathway in Cancer Biotherapy,” Molecular Cancer 19, no. 1 (2020): 136.

[132] E. N. Chin, A. Sulpizio, and L. L. Lairson, “Targeting STING to Promote Antitumor Immunity,” Trends in Cell Biology 33, no. 3 (2023): 189-203.

[133] R. Amadio, G. M. Piperno, and F. Benvenuti, “Self-DNA Sensing by cGAS-STING and TLR9 in Autoimmunity: Is the Cytoskeleton in Control?,” Frontiers in immunology 12 (2021): 657344.

[134] J. Rehwinkel and M. U. Gack, “RIG-I-Like Receptors: Their Regulation and Roles in RNA Sensing,” Nature Reviews Immunology 20, no. 9 (2020): 537-551.

[135] J. Song, M. Li, C. Li, et al., “Friend or Foe: RIG- I Like Receptors and Diseases,” Autoimmunity Reviews 21, no. 10 (2022): 103161.

[136] R. C. Widau, A. D. Parekh, M. C. Ranck, et al., “RIG-I-Like Receptor LGP2 Protects Tumor Cells From Ionizing Radiation,” PNAS 111, no. 4 (2014): E484-E491.

[137] Y. Wu, X. Wu, L. Wu, et al., “The Anticancer Functions of RIG-I-Like Receptors, RIG-I and MDA5, and Their Applications in Cancer Therapy,” Translational Research 190 (2017): 51-60.

[138] IRF3 and IRF7 Require SIRT1 for Liquid-liquid Phase Separation and Transactivation of IFN-1. Nature Immunology 2022; 23(8): 1144-1145.

[139] K. H. Simons, H. A. B. Peters, J. W. Jukema, et al., “A Protective Role of IRF3 and IRF7 Signalling Downstream TLRs in the Development of Vein Graft Disease via Type I Interferons,” Journal of Internal Medicine 282, no. 6 (2017): 522-536.

[140] S. Uematsu and S. Akira, “Toll-Like Receptors and Type I Interferons,” Journal of Biological Chemistry 282, no. 21 (2007): 15319-15323.

[141] K. Miyake, T. Shibata, U. Ohto, et al., “Mechanisms Controlling Nucleic Acid-Sensing Toll-Like Receptors,” International Immunology 30, no. 2 (2018): 43-51.

[142] S. Kim, L. Li, Z. Maliga, et al., “Anticancer Flavonoids Are Mouse-selective STING Agonists,” ACS Chemical Biology 8, no. 7 (2013): 1396-1401.

[143] X. Sun, Y. Zhang, J. Li, et al., “Amplifying STING Activation by Cyclic Dinucleotide-manganese Particles for Local and Systemic Cancer Metalloimmunotherapy,” Nature Nanotechnology 16, no. 11 (2021): 1260-1270.

[144] G. Schiavoni, A. Sistigu, M. Valentini, et al., “Cyclophosphamide Synergizes With Type I Interferons Through Systemic Dendritic Cell Reactivation and Induction of Immunogenic Tumor Apoptosis,” Cancer Research 71, no. 3 (2011): 768-778.

[145] M. Gyöngyösi, D. Lukovic, K. Zlabinger, et al., “Liposomal Doxorubicin Attenuates Cardiotoxicity via Induction of Interferon-related DNA Damage Resistance,” Cardiovascular Research 116, no. 5 (2020): 970-982.

[146] J. Wu and Z. J. Chen, “Innate Immune Sensing and Signaling of Cytosolic Nucleic Acids,” Annual Review of Immunology 32 (2014): 461-488.

[147] A. Zevini, D. Olagnier, and J. Hiscott, “Crosstalk Between Cytoplasmic RIG-I and STING Sensing Pathways,” Trends in Immunology 38, no. 3 (2017): 194-205.

[148] L. B. Ivashkiv and L. T. Donlin, “Regulation of Type I Interferon Responses,” Nature Reviews Immunology 14, no. 1 (2014): 36-49.

[149] G. R. Stark and J. E. Darnell, “The JAK-STAT Pathway at Twenty,” Immunity 36, no. 4 (2012): 503-514.

[150] P. J. Hertzog and B. R. G. Williams, “Fine Tuning Type I Interferon Responses,” Cytokine & Growth Factor Reviews 24, no. 3 (2013): 217-225.

[151] K. Chen, J. Liu, and X. Cao, “Regulation of Type I Interferon Signaling in Immunity and Inflammation: A Comprehensive Review,” Journal of Autoimmunity 83 (2017): 1-11.

[152] Y. J. Crow and D. B. Stetson, “The Type I Interferonopathies: 10 Years On,” Nature Reviews Immunology 22, no. 8 (2022): 471-483.

[153] C. Papewalis, B. Jacobs, M. Wuttke, et al., “IFN-alpha Skews Monocytes Into CD56+-Expressing Dendritic Cells With Potent Functional Activities in Vitro and in Vivo,” Journal of Immunology 180, no. 3 (2008): 1462-1470.

[154] E. Duong, T. B. Fessenden, E. Lutz, et al., “Type I Interferon Activates MHC Class I-Dressed CD11b+ Conventional Dendritic Cells to Promote Protective Anti-tumor CD8+ T Cell Immunity,” Immunity 55, no. 2 (2022): 308-323.

[155] M. Kuka, M. De Giovanni, and M. Iannacone, “The Role of Type I Interferons in CD4+ T Cell Differentiation,” Immunology Letters 215 (2019): 19-23.

[156] S. A. Barnes, K. M. Audsley, H. V. Newnes, et al., “Type I Interferon Subtypes Differentially Activate the Anti-Leukaemic Function of Natural Killer Cells,” Frontiers in immunology 13 (2022): 1050718.

[157] K. Alicea-Torres, E. Sanseviero, J. Gui, et al., “Immune Suppressive Activity of Myeloid-derived Suppressor Cells in Cancer Requires Inactivation of the Type I Interferon Pathway,” Nature Communications 12, no. 1 (2021): 1717.

[158] S. Vitale, V. Russo, B. Dettori, et al., “Type I Interferons Induce Peripheral T Regulatory Cell Differentiation Under Tolerogenic Conditions,” International Immunology 33, no. 2 (2021): 59-77.

[159] S. Li, B. Mirlekar, B. M. Johnson, et al., “STING-induced Regulatory B Cells Compromise NK Function in Cancer Immunity,” Nature 610, no. 7931 (2022): 373-380.

[160] E. Müller, M. Speth, P. F. Christopoulos, et al., “Both Type I and Type II Interferons Can Activate Antitumor M1 Macrophages When Combined with TLR Stimulation,” Frontiers in immunology 9 (2018): 2520.

[161] G. P. Dunn, C. M. Koebel, and R. D. Schreiber, “Interferons, Immunity and Cancer Immunoediting,” Nature Reviews Immunology 6, no. 11 (2006): 836-848.

[162] G. P. Dunn, A. T. Bruce, K. C. F. Sheehan, et al., “A Critical Function for Type I Interferons in Cancer Immunoediting,” Nature Immunology 6, no. 7 (2005): 722-729.

[163] I. Rusinova, S. Forster, S. Yu, et al., “Interferome v2.0: An Updated Database of Annotated Interferon-Regulated Genes,” Nucleic Acids Res. 41, no. Database issue (2013): D1040-D1046.

[164] M. von Locquenghien, C. Rozalén, and T. Celià-Terrassa, “Interferons in Cancer Immunoediting: Sculpting Metastasis and Immunotherapy Response,” Journal of Clinical Investigation 131, no. 1 (2021): e143296.

[165] M. F. McCarty, D. Bielenberg, C. Donawho, et al., “Evidence for the Causal Role of Endogenous Interferon-alpha/Beta in the Regulation of Angiogenesis, Tumorigenicity, and Metastasis of Cutaneous Neoplasms,” Clinical & Experimental Metastasis 19, no. 7 (2002): 609-615.

[166] M. Yi, X. Zheng, M. Niu, et al., “Combination Strategies With PD-1/PD-L1 Blockade: Current Advances and Future Directions,” Molecular cancer 21, no. 1 (2022): 28.

[167] A. Ribas and J. D. Wolchok, “Cancer Immunotherapy Using Checkpoint Blockade,” Science 359, no. 6382 (2018): 1350-1355.

[168] P. T. Nghiem, S. Bhatia, E. J. Lipson, et al., “PD-1 Blockade With Pembrolizumab in Advanced Merkel-Cell Carcinoma,” New England Journal of Medicine 374, no. 26 (2016): 2542-2552.

[169] D. T. Le, J. N. Durham, K. N. Smith, et al., “Mismatch Repair Deficiency Predicts Response of Solid Tumors to PD-1 Blockade,” Science 357, no. 6349 (2017): 409-413.

[170] Z. Eroglu, J. M. Zaretsky, S. Hu-Lieskovan, et al., “High Response Rate to PD-1 Blockade in Desmoplastic Melanomas,” Nature 553, no. 7688 (2018): 347-350.

[171] E. B. Garon, N. A. Rizvi, R. Hui, et al., “Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer,” New England Journal of Medicine 372, no. 21 (2015): 2018-2028.

[172] R. L. Ferris, G. Blumenschein, J. Fayette, et al., “Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck,” New England Journal of Medicine 375, no. 19 (2016): 1856-1867.

[173] J. E. Rosenberg, J. Hoffman-Censits, T. Powles, et al., “Atezolizumab in Patients With Locally Advanced and Metastatic Urothelial Carcinoma Who Have Progressed Following Treatment with Platinum-Based Chemotherapy: A Single-Arm, Multicentre, Phase 2 Trial,” Lancet 387, no. 10031 (2016): 1909-1920.

[174] J. Bellmunt, R. de Wit, D. J. Vaughn, et al., “Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma,” New England Journal of Medicine 376, no. 11 (2017): 1015-1026.

[175] H. M. Kluger, H. A. Tawbi, M. L. Ascierto, et al., “Defining Tumor Resistance to PD-1 Pathway Blockade: Recommendations From the First Meeting of the SITC Immunotherapy Resistance Taskforce,” Journal for ImmunoTherapy of Cancer 8, no. 1 (2020): e000398.

[176] M. B. Atkins, F. S. Hodi, J. A. Thompson, et al., “Pembrolizumab plus Pegylated Interferon Alfa-2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results From the Phase Ib KEYNOTE-029 Study,” Clinical Cancer Research 24, no. 8 (2018): 1805-1815.

[177] D. Davar, H. Wang, J.-M. Chauvin, et al., “Phase Ib/II Study of Pembrolizumab and Pegylated-Interferon Alfa-2b in Advanced Melanoma,” Journal of Clinical Oncology 36, no. 35 (2018): 3450-3458.

[178] Y. G. Najjar, D. McCurry, H. Lin, et al., “Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma,” Clinical Cancer Research 27, no. 15 (2021): 4195-4204.

[179] J. Cook, K.-W. Peng, T. E. Witzig, et al., “Clinical Activity of Single-Dose Systemic Oncolytic VSV Virotherapy in Patients With Relapsed Refractory T-Cell Lymphoma,” Blood Advances 6, no. 11 (2022): 3268-3279.

[180] M. K. van der Kooij, E. M. E. Verdegaal, M. Visser, et al., “Phase I/II Study Protocol to Assess Safety and Efficacy of Adoptive Cell Therapy With anti-PD-1 Plus Low-dose Pegylated-Interferon-Alpha in Patients With Metastatic Melanoma Refractory to Standard of Care Treatments: The ACTME Trial,” BMJ Open 10, no. 11 (2020): e044036.

[181] B. Hu, M. Yu, X. Ma, et al., “IFNα Potentiates Anti-PD-1 Efficacy by Remodeling Glucose Metabolism in the Hepatocellular Carcinoma Microenvironment,” Cancer discovery 12, no. 7 (2022): 1718-1741.

[182] J. Uehara, T. Ohkuri, A. Kosaka, et al., “Intratumoral Injection of IFN-β Induces Chemokine Production in Melanoma and Augments the Therapeutic Efficacy of Anti-PD-L1 mAb,” Biochemical and Biophysical Research Communications 490, no. 2 (2017): 521-527.

[183] P. A. Ott, Y.-J. Bang, P.-P. SA, et al., “T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated with Pembrolizumab across 20 Cancers: KEYNOTE-028,” Journal of Clinical Oncology 37, no. 4 (2019): 318-327.

[184] A. M. Goodman, S. Kato, L. Bazhenova, et al., “Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers,” Molecular Cancer Therapeutics 16, no. 11 (2017): 2598-2608.

[185] S. Maleki Vareki, “High and Low Mutational Burden Tumors versus Immunologically Hot and Cold Tumors and Response to Immune Checkpoint Inhibitors,” Journal for ImmunoTherapy of Cancer 6, no. 1 (2018): 157.

[186] D. Y. Torrejon, G. Abril-Rodriguez, A. S. Champhekar, et al., “Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade,” Cancer Discovery 10, no. 8 (2020): 1140-1157.

[187] J. S. O'Donnell, G. V. Long, R. A. Scolyer, et al., “Resistance to PD1/PDL1 Checkpoint Inhibition,” Cancer Treatment Reviews 52 (2017): 71-81.

[188] J. M. Pitt, M. Vétizou, R. Daillère, et al., “Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors,” Immunity 44, no. 6 (2016): 1255-1269.

[189] K.-P. Hopfner and V. Hornung, “Molecular Mechanisms and Cellular Functions of cGAS-STING Signalling,” Nature Reviews Molecular Cell Biology 21, no. 9 (2020): 501-521.

[190] M. Schmid, P. Fischer, M. Engl, et al., “The Interplay Between Autophagy and cGAS-STING Signaling and Its Implications for Cancer,” Frontiers in Immunology 15 (2024): 1356369.

[191] E. A. Lutz, Y. Agarwal, N. Momin, et al., “Alum-anchored Intratumoral Retention Improves the Tolerability and Antitumor Efficacy of Type I Interferon Therapies,” PNAS 119, no. 36 (2022): e2205983119.

[192] N. Tsuchiya, R. Zhang, T. Iwama, et al., “Type I Interferon Delivery by iPSC-Derived Myeloid Cells Elicits Antitumor Immunity via XCR1+ Dendritic Cells,” Cell Reports 29, no. 1 (2019): 162-175.

[193] Y. V. Katlinskaya, K. V. Katlinski, Q. Yu, et al., “Suppression of Type I Interferon Signaling Overcomes Oncogene-Induced Senescence and Mediates Melanoma Development and Progression,” Cell reports 15, no. 1 (2016): 171-180.

[194] M. W. LaFleur, T. H. Nguyen, M. A. Coxe, et al., “PTPN2 regulates the Generation of Exhausted CD8+ T Cell Subpopulations and Restrains Tumor Immunity,” Nature Immunology 20, no. 10 (2019): 1335-1347.

[195] N. Nigam, B. Bernard, S. Sevilla, et al., “SMYD3 represses Tumor-intrinsic Interferon Response in HPV-negative Squamous Cell Carcinoma of the Head and Neck,” Cell Reports 42, no. 7 (2023): 112823.

[196] I. A. Elcheva, C. P. Gowda, D. Bogush, et al., “IGF2BP family of RNA-binding Proteins Regulate Innate and Adaptive Immune Responses in Cancer Cells and Tumor Microenvironment,” Frontiers in Immunology 14 (2023): 1224516.

[197] G. Zhang, P. Jiang, W. Tang, et al., “CPT1A induction Following Epigenetic Perturbation Promotes MAVS Palmitoylation and Activation to Potentiate Antitumor Immunity,” Molecular Cell 83, no. 23 (2023): 4370-4385.

[198] Z. Li, Q. Zhang, Z. Li, et al., “Branched Glycopolymer Prodrug-derived Nanoassembly Combined With a STING Agonist Activates an Immuno-supportive Status to Boost Anti-PD-L1 Antibody Therapy,” Acta Pharmacologica Sinica B 14, no. 5 (2024): 2194-2209.

[199] K. Knox, D. Jeltema, N. Dobbs, et al., “Dynamic STING Repression Orchestrates Immune Cell Development and Function,” Science Immunology 10, no. 105 (2025): eado9933.

[200] S. A. Perera, J. E. Kopinja, Y. Ma, et al., “STimulator of INterferon Genes Agonism Accelerates Antitumor Activity in Poorly Immunogenic Tumors,” Molecular Cancer Therapeutics 21, no. 2 (2022): 282-293.

[201] C. R. Ager, A. Boda, K. Rajapakshe, et al., “High Potency STING Agonists Engage Unique Myeloid Pathways to Reverse Pancreatic Cancer Immune Privilege,” Journal for ImmunoTherapy of Cancer 9, no. 8 (2021): e003246.

[202] W. Chang, M. D. Altman, C. A. Lesburg, et al., “Discovery of MK-1454: A Potent Cyclic Dinucleotide Stimulator of Interferon Genes Agonist for the Treatment of Cancer,” Journal of Medicinal Chemistry 65, no. 7 (2022): 5675-5689.

[203] K.-C. Huang, D. Chanda, S. McGrath, et al., “Pharmacologic Activation of STING in the Bladder Induces Potent Antitumor Immunity in Non-Muscle Invasive Murine Bladder Cancer,” Molecular Cancer Therapeutics 21, no. 6 (2022): 914-924.

[204] K. L. Morel, A. V. Sheahan, D. L. Burkhart, et al., “EZH2 inhibition Activates a dsRNA-STING-Interferon Stress Axis That Potentiates Response to PD-1 Checkpoint Blockade in Prostate Cancer,” Nature Cancer 2, no. 4 (2021): 444-456.

[205] I. Mender, A. Zhang, Z. Ren, et al., “Telomere Stress Potentiates STING-Dependent Anti-Tumor Immunity,” Cancer Cell 38, no. 3 (2020): 400-411.e6.

[206] D. Wan, Z. Bai, Y. Zhang, et al., “Simultaneous Enhancement of Cellular and Humoral Immunity by the Lymph Node-targeted Cholesterolized TLR7 Agonist Liposomes,” Acta Pharmacologica Sinica B 14, no. 10 (2024): 4577-4590.

[207] J. Asami and T. Shimizu, “Structural and Functional Understanding of the Toll-Like Receptors,” Protein Science 30, no. 4 (2021): 761-772.

[208] T. Kawai, M. Ikegawa, D. Ori, et al., “Decoding Toll-Like Receptors: Recent Insights and Perspectives in Innate Immunity,” Immunity 57, no. 4 (2024): 649-673.

[209] D. J. Perkins and S. N. Vogel, “Space and Time: New Considerations About the Relationship Between Toll-Like Receptors (TLRs) and Type I Interferons (IFNs),” Cytokine 74, no. 2 (2015): 171-174.

[210] Y. Takeda, K. Kataoka, J. Yamagishi, et al., “A TLR3-Specific Adjuvant Relieves Innate Resistance to PD-L1 Blockade Without Cytokine Toxicity in Tumor Vaccine Immunotherapy,” Cell Reports 19, no. 9 (2017): 1874-1887.

[211] M. Smith, E. García-Martínez, M. R. Pitter, et al., “Trial Watch: Toll-Like Receptor Agonists in Cancer Immunotherapy,” Oncoimmunology 7, no. 12 (2018): e1526250.

[212] K. J. Hiam-Galvez, B. M. Allen, and M. H. Spitzer, “Systemic Immunity in Cancer,” Nature Reviews Cancer 21, no. 6 (2021): 345-359.

[213] Y. Ota, Y. Nagai, Y. Hirose, et al., “DSP-0509, a Systemically Available TLR7 Agonist, Exhibits Combination Effect With Immune Checkpoint Blockade by Activating Anti-tumor Immune Effects,” Frontiers in immunology 14 (2023): 1055671.

[214] C. Su, C. L. Kent, M. Pierpoint, et al., “Enhancing Radiotherapy Response via Intratumoral Injection of the TLR9 Agonist CpG to Stimulate CD8 T Cells in an Autochthonous Mouse Model of Sarcoma,” BioRxiv (2024): 20240103573968.

[215] Y. Jin, Y. Zhuang, X. Dong, et al., “Development of CpG Oligodeoxynucleotide TLR9 Agonists in Anti-Cancer Therapy,” Expert Review of Anticancer Therapy 21, no. 8 (2021): 841-851.

[216] Q. Li, J. Ren, W. Liu, et al., “CpG Oligodeoxynucleotide Developed to Activate Primate Immune Responses Promotes Antitumoral Effects in Combination With a Neoantigen-Based mRNA Cancer Vaccine,” Drug Design, Development and Therapy 15 (2021): 3953-3963.

[217] S. Wang, J. Campos, M. Gallotta, et al., “Intratumoral Injection of a CpG Oligonucleotide Reverts Resistance to PD-1 Blockade by Expanding Multifunctional CD8+ T Cells,” PNAS 113, no. 46 (2016): E7240-E7249.

[218] J. Gutierrez-Merino, B. Isla, T. Combes, et al., “Beneficial Bacteria Activate Type-I Interferon Production via the Intracellular Cytosolic Sensors STING and MAVS,” Gut Microbes 11, no. 4 (2020): 771-788.

[219] X. Yang, X. Cheng, Y. Tang, et al., “The Role of Type 1 Interferons in Coagulation Induced by Gram-negative Bacteria,” Blood 135, no. 14 (2020): 1087-1100.

[220] D. S. Leventhal, A. Sokolovska, N. Li, et al., “Immunotherapy With Engineered Bacteria by Targeting the STING Pathway for Anti-tumor Immunity,” Nature Communications 11, no. 1 (2020): 2739.

[221] L. Kornstädt, S. Pierre, A. Weigert, et al., “Bacterial and Fungal Toll-Like Receptor Activation Elicits Type I IFN Responses in Mast Cells,” Frontiers in immunology 11 (2020): 607048.

[222] T. André, K.-K. Shiu, T. W. Kim, et al., “Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer,” New England Journal of Medicine 383, no. 23 (2020): 2207-2218.

[223] M. J. Overman, R. McDermott, J. L. Leach, et al., “Nivolumab in Patients With Metastatic DNA Mismatch Repair-deficient or Microsatellite Instability-high Colorectal Cancer (CheckMate 142): An Open-Label, Multicentre, Phase 2 Study,” The Lancet Oncology 18, no. 9 (2017): 1182-1191.

[224] S.-S. Jiang, Y.-L. Xie, X.-Y. Xiao, et al., “Fusobacterium nucleatum-Derived Succinic Acid Induces Tumor Resistance to Immunotherapy in Colorectal Cancer,” Cell Host & Microbe 31, no. 5 (2023): 781-797.

[225] W. Si, H. Liang, J. Bugno, et al., “Lactobacillus rhamnosus GG Induces cGAS/STING- Dependent Type I Interferon and Improves Response to Immune Checkpoint Blockade,” Gut 71, no. 3 (2022): 521-533.

[226] X. Kong, P. Gao, J. Wang, et al., “Advances of Medical Nanorobots for Future Cancer Treatments,” Journal of Hematology & Oncology 16, no. 1 (2023): 74.

[227] Y. Zhang, Z. Fang, D. Pan, et al., “Dendritic Polymer-Based Nanomedicines Remodel the Tumor Stroma: Improve Drug Penetration and Enhance Antitumor Immune Response,” Advanced Materials 36, no. 25 (2024): 2401304.

[228] H. Li, Y. Feng, Q. Luo, et al., “Stimuli-Activatable Nanomedicine Meets Cancer,” Theranostics 13, no. 15 (2023): 5386-5417.

[229] L. Lin, Z. Fang, G. Liu, et al., “Prodrug-based Combinational Nanomedicine Remodels Lipid Metabolism for Reinforced Ferroptosis and Immune Activation,” Acta Pharmacologica Sinica B 15, no. 5 (2025): 2746-2763.

[230] Y. Li, Y. Wu, Z. Fang, et al., “Dendritic Nanomedicine With Boronate Bonds for Augmented Chemo-Immunotherapy via Synergistic Modulation of Tumor Immune Microenvironment,” Advanced Materials 36, no. 2 (2024): 2307263.

[231] Y. Li, X. Shen, H. Ding, et al., “Dendritic Nanomedicine Enhances Chemo-Immunotherapy by Disturbing Metabolism of Cancer-Associated Fibroblasts for Deep Penetration and Activating Function of Immune Cells,” Acta Pharmacologica Sinica B 14, no. 8 (2024): 3680-3696.

[232] Y. Zhang, J. Zhou, Y. Wang, et al., “Stimuli-responsive Polymer-Dasatinib Prodrug to Reprogram Cancer-Associated Fibroblasts for Boosted Immunotherapy,” Journal of Control Release 381 (2025): 113606.

[233] P. Gao, Z. Duan, G. Xu, et al., “Harnessing and Mimicking Bacterial Features to Combat Cancer: From Living Entities to Artificial Mimicking Systems,” Advanced Materials 36, no. 35 (2024): 2405075.

[234] P. Gao, X. Xiao, Z. Li, et al., “Low-Irradiance PDT Enhances Tumor Accumulation of 2ME-based Nano-Prodrug to Achieve Metastasis Inhibition via HIF-1α Suppression,” European Polymer Journal 203 (2024): 112693.

[235] X. Wang, J. Chen, Z. Li, et al., “A Branched Polymer-based Agent for Efficient and Precise Targeting of Fibrosis Diseases by Magnetic Resonance Imaging,” Journal of Control Release 373 (2024): 905-916.

[236] D. Hu, Y. Li, R. Li, et al., “Recent Advances in Reactive Oxygen Species (ROS)-Responsive Drug Delivery Systems for Photodynamic Therapy of Cancer,” Acta Pharmacologica Sinica B 14, no. 12 (2024): 5106-5131.

[237] L. Yang, Y. Wang, Y. Song, et al., “Metal Coordination Nanotheranostics Mediated by Nucleoside Metabolic Inhibitors Potentiate STING Pathway Activation for Cancer Metalloimmunotherapy,” Journal of Control Release 370 (2024): 354-366.

[238] Y. Lin, X. Wang, S. He, et al., “Immunostimulatory Gene Therapy Combined With Checkpoint Blockade Reshapes Tumor Microenvironment and Enhances Ovarian Cancer Immunotherapy,” Acta Pharmacologica Sinica B 14, no. 2 (2024): 854-868.

[239] C. Hu, Y. Song, Y. Zhang, et al., “Sequential Delivery of PD-1/PD-L1 Blockade Peptide and IDO Inhibitor for Immunosuppressive Microenvironment Remodeling via an MMP-2 Responsive Dual-Targeting Liposome,” Acta Pharmacologica Sinica B 13, no. 5 (2023): 2176-2187.

[240] B. Zhang, J. Zhang, Y. Li, et al., “Situ STING-Activating Nanovaccination With TIGIT Blockade for Enhanced Immunotherapy of Anti-PD-1-Resistant Tumors,” Advanced Materials 35, no. 24 (2023): 2300171.

[241] Q. Feng, J. Chen, J. Huang, et al., “A Redox-responsive Nanosystem to Suppress Chemoresistant Lung Cancer Through Targeting STAT3,” Journal of Control Release 363 (2023): 349-360.

[242] Y. Zhang, J. Zhou, X. Chen, et al., “Modulating Tumor-Stromal Crosstalk via a Redox-Responsive Nanomedicine for Combination Tumor Therapy,” Journal of Control Release 356 (2023): 525-541.

[243] S. He, L. Wang, D. Wu, et al., “Dual-responsive Supramolecular Photodynamic Nanomedicine with Activatable Immunomodulation for Enhanced Antitumor Therapy,” Acta Pharmacologica Sinica B 14, no. 2 (2024): 765-780.

[244] H. Cai, Y. Xiang, Y. Zeng, et al., “Cathepsin B-Responsive and Gadolinium-Labeled Branched Glycopolymer-PTX Conjugate-Derived Nanotheranostics for Cancer Treatment,” Acta Pharmacologica Sinica B 11, no. 2 (2021): 544-559.

[245] T. Nakamura, T. Sato, R. Endo, et al., “STING Agonist Loaded Lipid Nanoparticles Overcome Anti-PD-1 Resistance in Melanoma Lung Metastasis via NK Cell Activation,” Journal for ImmunoTherapy of Cancer 9, no. 7 (2021): e002852.

[246] D. Liu, S. Liang, K. Ma, et al., “Tumor Microenvironment-Responsive Nanoparticles Amplifying STING Signaling Pathway for Cancer Immunotherapy,” Advanced Materials (2023): 2304845.

[247] X. Li, Z. Duan, Z. Li, et al., “Dendritic Polymer-functionalized Nanomedicine Potentiates Immunotherapy via Lethal Energy Crisis-induced PD-L1 Degradation,” Biomaterials 302 (2023): 122294.

[248] S. Gettinger, J. Choi, K. Hastings, et al., “Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer,” Cancer Discovery 7, no. 12 (2017): 1420-1435.

[249] V. Anagnostou, K. N. Smith, P. M. Forde, et al., “Evolution of Neoantigen Landscape During Immune Checkpoint Blockade in Non-Small Cell Lung Cancer,” Cancer Discovery 7, no. 3 (2017): 264-276.

[250] N. K. Wolf, C. Blaj, L. K. Picton, et al., “Synergy of a STING Agonist and an IL-2 Superkine in Cancer Immunotherapy Against MHC I-deficient and MHC I+ Tumors,” PNAS 119, no. 22 (2022): e2200568119.

[251] S. Dvorkin, S. Cambier, H. E. Volkman, et al., “New Frontiers in the cGAS-STING Intracellular DNA-Sensing Pathway,” Immunity 57, no. 4 (2024): 718-730.

[252] K. J. Mackenzie, P. Carroll, C.-A. Martin, et al., “cGAS Surveillance of Micronuclei Links Genome Instability to Innate Immunity,” Nature 548, no. 7668 (2017): 461-465.

[253] M.-M. Hu and H.-B. Shu, “Mitochondrial DNA-triggered Innate Immune Response: Mechanisms and Diseases,” Cellular and Molecular Immunology 20, no. 12 (2023): 1403-1412.

[254] N. Dobbs, N. Burnaevskiy, D. Chen, et al., “STING Activation by Translocation From the ER Is Associated With Infection and Autoinflammatory Disease,” Cell Host & Microbe 18, no. 2 (2015): 157-168.

[255] X. Wang, J. E. Schoenhals, A. Li, et al., “Suppression of Type I IFN Signaling in Tumors Mediates Resistance to Anti-PD-1 Treatment That Can Be Overcome by Radiotherapy,” Cancer Research 77, no. 4 (2017): 839-850.

[256] L. M. Snell, T. L. McGaha, and D. G. Brooks, “Type I Interferon in Chronic Virus Infection and Cancer,” Trends in Immunology 38, no. 8 (2017): 542-557.

[257] C. Zheng, J. Wang, Y. Zhou, et al., “IFNα-induced BST2+ Tumor-associated Macrophages Facilitate Immunosuppression and Tumor Growth in Pancreatic Cancer by ERK-CXCL7 Signaling,” Cell Reports 43, no. 4 (2024): 114088.

[258] S. Tanwar, C. Oguz, A. Metidji, et al., “Type I IFN Signaling in T Regulatory Cells Modulates Chemokine Production and Myeloid Derived Suppressor Cells Trafficking During EAE,” Journal of Autoimmunity 115 (2020): 102525.

[259] L. Pang, O. W. H. Yeung, K. T. P. Ng, et al., “Postoperative Plasmacytoid Dendritic Cells Secrete IFNα to Promote Recruitment of Myeloid-Derived Suppressor Cells and Drive Hepatocellular Carcinoma Recurrence,” Cancer Research 82, no. 22 (2022): 4206-4218.

[260] W. Qiao, J. Chen, H. Zhou, et al., “A Single-Atom Manganese Nanozyme Mn-N/C Promotes Anti-Tumor Immune Response via Eliciting Type I Interferon Signaling,” Advanced Science (Weinh) 11, no. 14 (2024): 2305979.

[261] P. Trono, A. Tocci, B. Palermo, et al., “hMENA Isoforms Regulate Cancer Intrinsic Type I IFN Signaling and Extrinsic Mechanisms of Resistance to Immune Checkpoint Blockade in NSCLC,” Journal for ImmunoTherapy of Cancer 11, no. 8 (2023): e006913.

[262] A. V. Bazhin, K. von Ahn, J. Fritz, et al., “Interferon-α Up-Regulates the Expression of PD-L1 Molecules on Immune Cells through STAT3 and p38 Signaling,” Frontiers in Immunology 9 (2018): 2129.

[263] Y. Morimoto, T. Kishida, S.-i Kotani, et al., “Interferon-β Signal May Up-Regulate PD-L1 Expression Through IRF9-Dependent and Independent Pathways in Lung Cancer Cells,” Biochemical and Biophysical Research Communications 507, no. 1 (2018): 330-336.

[264] R. Wang, S. He, J. Long, et al., “Emerging Therapeutic Frontiers in Cancer: Insights Into Posttranslational Modifications of PD-1/PD-L1 and Regulatory Pathways,” Experimental Hematology & Oncology 13, no. 1 (2024): 46.

[265] X. Chen, L.-J. Chen, X.-F. Peng, et al., “Anti-PD-1/PD-L1 Therapy for Colorectal Cancer: Clinical Implications and Future Considerations,” Translational Oncology 40 (2024): 101851.

[266] X. Zhou, Z. Yao, H. Bai, et al., “Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitor-Based Combination Therapies in Clinical Trials: A Systematic Review and Meta-Analysis,” The Lancet Oncology 22, no. 9 (2021): 1265-1274.

[267] Y. Wang, D. Pattarayan, H. Huang, et al., “Systematic Investigation of Chemo-Immunotherapy Synergism to Shift Anti-PD-1 Resistance in Cancer,” Nature Communications 15, no. 1 (2024): 3178.

[268] L. Luo, Y. Qi, H. Zhong, et al., “GSH-sensitive Polymeric Prodrug: Synthesis and Loading With Photosensitizers as Nanoscale Chemo-photodynamic Anti-cancer Nanomedicine,” Acta Pharmacologica Sinica B 12, no. 1 (2022): 424-436.

[269] G. M. Boukhaled, S. Harding, and D. G. Brooks, “Opposing Roles of Type I Interferons in Cancer Immunity,” Annual Review of Pathology 16 (2021): 167-198.

[270] G. M. Boukhaled, R. Gadalla, H. J. Elsaesser, et al., “Pre-Encoded Responsiveness to Type I Interferon in the Peripheral Immune System Defines Outcome of PD1 Blockade Therapy,” Nature Immunology 23, no. 8 (2022): 1273-1283.

[271] T. S. Sumida, S. Dulberg, J. C. Schupp, et al., “Type I Interferon Transcriptional Network Regulates Expression of Coinhibitory Receptors in human T Cells,” Nature Immunology 23, no. 4 (2022): 632-642.

[272] H. Cheon, Y. Wang, S. M. Wightman, et al., “How Cancer Cells Make and Respond to Interferon-I,” Trends in Cancer 9, no. 1 (2023): 83-92.

[273] S. Peuget, X. Zhou, and G. Selivanova, “Translating p53-based Therapies for Cancer Into the Clinic,” Nature Reviews Cancer 24, no. 3 (2024): 192-215.

[274] C. Muñoz-Fontela, S. Macip, L. Martínez-Sobrido, et al., “Transcriptional Role of p53 in Interferon-Mediated Antiviral Immunity,” Journal of Experimental Medicine 205, no. 8 (2008): 1929-1938.

[275] B. Wang, J. Han, J. H. Elisseeff, et al., “The Senescence-associated Secretory Phenotype and Its Physiological and Pathological Implications,” Nature Reviews Molecular Cell Biology (2024): 1-21.

[276] T. M. Loo, K. Miyata, Y. Tanaka, et al., “Cellular Senescence and Senescence-Associated Secretory Phenotype via the cGAS-STING Signaling Pathway in Cancer,” Cancer Science 111, no. 2 (2020): 304-311.

[277] D. Ahmed and E. Cassol, “Role of Cellular Metabolism in Regulating Type I Interferon Responses: Implications for Tumour Immunology and Treatment,” Cancer Letters 409 (2017): 20-29.

[278] I. Ben-Sahra and B. D. Manning, “mTORC1 signaling and the Metabolic Control of Cell Growth,” Current Opinion in Cell Biology 45 (2017): 72-82.

[279] Y.-H. Yeh, H.-F. Hsiao, Y.-C. Yeh, et al., “Inflammatory Interferon Activates HIF-1α-mediated Epithelial-to-mesenchymal Transition via PI3K/AKT/mTOR Pathway,” Journal of Experimental & Clinical Cancer Research 37, no. 1 (2018): 70.

[280] Y. Li, A. Sharma, and I. G. H. Schmidt-Wolf, “Evolving Insights Into the Improvement of Adoptive T-cell Immunotherapy Through PD-1/PD-L1 Blockade in the Clinical Spectrum of Lung Cancer,” Molecular Cancer 23, no. 1 (2024): 80.

[281] G. T. Gibney, L. M. Weiner, and M. B. Atkins, “Predictive Biomarkers for Checkpoint Inhibitor-Based Immunotherapy,” The Lancet Oncology 17, no. 12 (2016): e542-e551.

[282] C. S. K. Leung and B. J. Van den Eynde, “Combining Personalized Neoantigen Vaccination With Chemotherapy and Anti-PD-1 to Treat NSCLC,” Cancer Cell 40, no. 9 (2022): 903-905.

[283] J.-W. Cui, Y. Li, Y. Yang, et al., “Tumor Immunotherapy Resistance: Revealing the Mechanism of PD-1 /PD-L1-Mediated Tumor Immune Escape,” Biomedicine & Pharmacotherapy 171 (2024): 116203.

[284] S. Chakraborty, J. Ye, H. Wang, et al., “Application of Toll-Like Receptors (TLRs) and Their Agonists in Cancer Vaccines and Immunotherapy,” Frontiers in immunology 14 (2023): 1227833.

[285] D. Davar, A. K. Dzutsev, J. A. McCulloch, et al., “Fecal Microbiota Transplant Overcomes Resistance to Anti-PD-1 Therapy in Melanoma Patients,” Science 371, no. 6529 (2021): 595-602.

[286] J. Jia, X. Wang, X. Lin, et al., “Engineered Microorganisms for Advancing Tumor Therapy,” Advanced Materials (2024): 2313389.

[287] T. Yu, Z. Liu, Q. Tao, et al., “Targeting Tumor-intrinsic SLC16A3 to Enhance Anti-PD-1 Efficacy via Tumor Immune Microenvironment Reprogramming,” Cancer Letters 589 (2024): 216824.

[288] A. J. Schoenfeld and M. D. Hellmann, “Acquired Resistance to Immune Checkpoint Inhibitors,” Cancer Cell 37, no. 4 (2020): 443-455.

[289] M. Yi, T. Li, M. Niu, et al., “Exploiting Innate Immunity for Cancer Immunotherapy,” Molecular Cancer 22, no. 1 (2023): 187.

[290] A. Hu, L. Sun, H. Lin, et al., “Harnessing Innate Immune Pathways for Therapeutic Advancement in Cancer,” Signal Transduction and Targeted Therapy 9, no. 1 (2024): 68.

[291] Reactivity to Type I Interferon Is Key to Predict Cancer Immunotherapy Response. Nature Immunology; 23, no. (8) (2022): 1146-1147.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.