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Abstract
Immune checkpoint inhibitors have revolutionized the treatment landscape for various malignancies by enhancing the body's natural immune response against tumor cells. Targeting molecules such as CTLA-4 and PD-1/PD-L1, these therapies release the brakes on T-cell activation and proliferation. Despite impressive clinical outcomes in melanoma, lung cancer, and renal carcinoma, a significant proportion of patients exhibit primary or acquired resistance. This review delves into the molecular mechanisms of checkpoint blockade, discusses biomarkers predictive of response, and explores resistance pathways including immunoediting, tumor microenvironment immunosuppression, and upregulation of alternative checkpoints. Novel strategies to overcome resistance, such as combination therapies and personalized immunotherapeutics, are critically analyzed.
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Copyright (c) 2025 Ghadah Ali Al-Oudah, Wallaa Luay Alfalluji, Ahmed M N Al-Ajrash (Author)
This work is licensed under a Creative Commons Attribution 4.0 International License.
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References
- Li X, Shao C, Shi Y, Han W. Lessons learned from the blockade of immune checkpoints in cancer immunotherapy. J Hematol Oncol. 2018;11(1):31. doi:10.1186/s13045-018-0578-4
- Alsaafeen, B.H., Ali, B.R. & Elkord, E. Resistance mechanisms to immune checkpoint inhibitors: updated insights. Mol Cancer 24, 20 (2025). https://doi.org/10.1186/s12943-024-02212-7
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- Jardim DL, de Melo Gagliato D, Kurzrock R. Lessons From the Development of the Immune Checkpoint Inhibitors in Oncology. Integr Cancer Ther. 2018 Dec;17(4):1012-1015. doi: 10.1177/1534735418801524.
- Ahmed M. Checkpoint inhibitors: What gastroenterologists need to know. World J Gastroenterol. 2018 Dec 28;24(48):5433-5438. doi: 10.3748/wjg.v24.i48.5433.
- van Elsas MJ, van Hall T, van der Burg SH. Future Challenges in Cancer Resistance to Immunotherapy. Cancers (Basel). 2020 Apr 10;12(4):935. doi: 10.3390/cancers12040935.
- Chocarro de Erauso L, Zuazo M, Arasanz H, Bocanegra A, Hernandez C, Fernandez G, Garcia-Granda MJ, Blanco E, Vera R, Kochan G, Escors D. Resistance to PD-L1/PD-1 blockade immunotherapy. A tumor-intrinsic or tumor-extrinsic phenomenon? Frontiers in Pharmacology. 2020;11:441. doi:10.3389/fphar.2020.00441.
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References
Li X, Shao C, Shi Y, Han W. Lessons learned from the blockade of immune checkpoints in cancer immunotherapy. J Hematol Oncol. 2018;11(1):31. doi:10.1186/s13045-018-0578-4
Alsaafeen, B.H., Ali, B.R. & Elkord, E. Resistance mechanisms to immune checkpoint inhibitors: updated insights. Mol Cancer 24, 20 (2025). https://doi.org/10.1186/s12943-024-02212-7
Rodriguez-Pascual J, Ayuso-Sacido A, Belda-Iniesta C. Drug resistance in cancer immunotherapy: new strategies to improve checkpoint inhibitor therapies. Cancer Drug Resist. 2019;2(4):980-993. doi: 10.20517/cdr.2019.61
Nagasaki J, Ishino T, Togashi Y. Mechanisms of resistance to immune checkpoint inhibitors. Cancer Sci. 2022;113(10):3303-3312. doi:10.1111/cas.15497
Lisovska N. Multilevel mechanism of immune checkpoint inhibitor action in solid tumors: History, present issues and future development. Oncol Lett. 2022 Jun;23(6):190. Epub 2022 Apr 29. doi: 10.3892/ol.2022.13310.
Jardim DL, de Melo Gagliato D, Kurzrock R. Lessons From the Development of the Immune Checkpoint Inhibitors in Oncology. Integr Cancer Ther. 2018 Dec;17(4):1012-1015. doi: 10.1177/1534735418801524.
Ahmed M. Checkpoint inhibitors: What gastroenterologists need to know. World J Gastroenterol. 2018 Dec 28;24(48):5433-5438. doi: 10.3748/wjg.v24.i48.5433.
van Elsas MJ, van Hall T, van der Burg SH. Future Challenges in Cancer Resistance to Immunotherapy. Cancers (Basel). 2020 Apr 10;12(4):935. doi: 10.3390/cancers12040935.
Chocarro de Erauso L, Zuazo M, Arasanz H, Bocanegra A, Hernandez C, Fernandez G, Garcia-Granda MJ, Blanco E, Vera R, Kochan G, Escors D. Resistance to PD-L1/PD-1 blockade immunotherapy. A tumor-intrinsic or tumor-extrinsic phenomenon? Frontiers in Pharmacology. 2020;11:441. doi:10.3389/fphar.2020.00441.
Filipovic A, Miller G, Bolen J. Progress toward identifying exact proxies for predicting response to immunotherapies. Front Cell Dev Biol. 2020;8:155. doi:10.3389/fcell.2020.00155.