Immunotherapy in colorectal cancer
DOI:
https://doi.org/10.14748/dbef7r82Keywords:
immunotherapy, colorectal cancer (CRC), complete pathological response, microsatellite instability, genomic instability, targeted therapiesAbstract
Colorectal cancer is an oncological disease with high incidence and social significance. Despite advances in diagnostics and the multimodal approach to treatment, the prognosis for patients with advanced or metastatic disease remains poor. This necessitates a more in-depth study of tumor biology and the elucidation of various important pathogenetic factors for the development of the disease. Knowledge of genomic instability pathways enables tumor typing and the application of effective personalized treatment. Traditional therapeutic approaches are often associated with significant toxicity and resistance, which requires the search for more effective and tolerable medicinal products. The current article aims to review contemporary achievements and future directions in the field of immunotherapy for colorectal cancer, with a focus on mechanisms of action, clinical outcomes, and strategies for overcoming resistance.
References
[1] Dimitrova-Gospodinova E. Colorectal carcinoma. Medical University of Varna; 2018. (in Bulgarian).
[2] Dimitrova-Gospodinova E. Personalized approach in patients with colorectal carcinoma. Medical University of Varna; 2025. (in Bulgarian).
[3] Zgurova N, Tzaneva M. Pathways of colorectal carcinogenesis. Varna Med Forum. 2019;8(1):36-42. doi: 10.14748/vmf.v8i1.5641. DOI: https://doi.org/10.14748/vmf.v8i1.5641
[4] Milanova V, Ivanovska N, Dimitrova P. TLR2 elicits IL-17-mediated RANKL expression, IL-17, and OPG production in neutrophils from arthritic mice. Mediators Inflamm. 2014;2014:643406. doi: 10.1155/2014/643406. DOI: https://doi.org/10.1155/2014/643406
[5] Kang X, Zhang R, Kwong TN, et al. Serrated neoplasia in the colorectum: gut microbiota and molecular pathways. Gut Microbes. 2021 Jan-Dec;13(1):1-12. doi: 10.1080/19490976.2020.1863135. DOI: https://doi.org/10.1080/19490976.2020.1863135
[6] Li Q, Geng S, Luo H, et al. Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy. Signal Transduct Target Ther. 2024 Oct 7;9(1):266. doi: 10.1038/s41392-024-01953-7. DOI: https://doi.org/10.1038/s41392-024-01953-7
[7] Stjepanovic N, Moreira L, Carneiro F, et al. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2019 Oct 1;30(10):1558-1571. doi: 10.1093/annonc/mdz233. DOI: https://doi.org/10.1093/annonc/mdz233
[8] Weisenberger DJ, Siegmund KD, Campan M, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006 Jul;38(7):787-93. doi: 10.1038/ng1834. DOI: https://doi.org/10.1038/ng1834
[9] Huang Z, Yang M. Molecular Network of Colorectal Cancer and Current Therapeutic Options. Front Oncol. 2022 Apr 6;12:852927. doi: 10.3389/fonc.2022.852927. DOI: https://doi.org/10.3389/fonc.2022.852927
[10] Dunne PD, Arends MJ. Molecular pathological classification of colorectal cancer-an update. Virchows Arch. 2024 Feb;484(2):273-85. doi: 10.1007/s00428-024-03746-3. DOI: https://doi.org/10.1007/s00428-024-03746-3
[11] Cornista AM, Giolito MV, Baker K, et al. Colorectal Cancer Immunotherapy: State of the Art and Future Directions. Gastro Hep Adv. 2023;2(8):1103-1119. doi: 10.1016/j.gastha.2023.09.007. DOI: https://doi.org/10.1016/j.gastha.2023.09.007
[12] Hofheinz RD, Fokas E, Benhaim L, et al. Localised rectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2025 Sep;36(9):1007-1024. doi: 10.1016/j.annonc.2025.05.528. DOI: https://doi.org/10.1016/j.annonc.2025.05.528
[13] Andre T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009; 27(19):3109-16. doi: 10.1200/JCO.2008.20.6771. DOI: https://doi.org/10.1200/JCO.2008.20.6771
[14] Yoshino T, Cervantes A, Bando H, et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with metastatic colorectal cancer. ESMO Open. 2023 Jun;8(3):101558. doi: 10.1016/j.esmoop.2023.101558. DOI: https://doi.org/10.1016/j.esmoop.2023.101558
[15] Papamichael D, Audisio RA, Glimelius B, et al. Treatment of colorectal cancer in older patients: International Society of Geriatric Oncology (SIOG) consensus recommendations 2013. Ann Oncol. 2015 Mar;26(3):463-76. doi: 10.1093/annonc/mdu253. DOI: https://doi.org/10.1093/annonc/mdu253
[16] Cervantes A, Adam R, Roselló S, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023 Jan;34(1):10-32. doi: 10.1016/j.annonc.2022.10.003. DOI: https://doi.org/10.1016/j.annonc.2022.10.003
[17] Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20. doi: 10.1056/NEJMoa1500596. DOI: https://doi.org/10.1056/NEJMoa1500596
[18] Taieb J, Svrcek M, Cohen R, et al. Deficient mismatch repair/microsatellite unstable colorectal cancer: Diagnosis, prognosis and treatment. Eur J Cancer. 2022 Nov;175:136-157. doi: 10.1016/j.ejca.2022.07.020. DOI: https://doi.org/10.1016/j.ejca.2022.07.020
[19] Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413. doi: 10.1126/science.aan6733. DOI: https://doi.org/10.1126/science.aan6733
[20] Diaz LA Jr, Shiu KK, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022 May;23(5):659-670. doi: 10.1016/S1470-2045(22)00197-8. DOI: https://doi.org/10.1016/S1470-2045(22)00197-8
[21] Pharmacotherapeutic handbook of medical oncology. State Gazette. 2025 Apr 25. Issue 35. (in Bulgarian).
[22] Overman MJ, McDermott R, Leach JL, 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. Lancet Oncol. 2017 Sep;18(9):1182-1191. doi: 10.1016/S1470-2045(17)30422-9. DOI: https://doi.org/10.1016/S1470-2045(17)30422-9
[23] Chalabi M, Verschoor YL, Tan PB, et al. Neoadjuvant Immunotherapy in Locally Advanced Mismatch Repair-Deficient Colon Cancer. N Engl J Med. 2024 Jun 6;390(21):1949-58. doi: 10.1056/NEJMoa2400634. DOI: https://doi.org/10.1056/NEJMoa2400634
[24] de Gooyer PGM, Verschoor YL, van den Dungen LDW, et al. Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial. Nat Med. 2024 Nov;30(11):3284-90. doi: 10.1038/s41591-024-03250-w. DOI: https://doi.org/10.1038/s41591-024-03250-w
[25] Cercek A, Bachet JB, Capdevila J, et al. A Phase Two, Single-Arm, Open-Label Study with Dostarlimab Monotherapy in Participants with Untreated Stage II/III dMMR/MSI-H Locally Advanced Rectal Cancer (AZUR-1). Clin Colorectal Cancer. 2025 Jun;24(2):325-30. doi: 10.1016/j.clcc.2025.02.003. DOI: https://doi.org/10.1016/j.clcc.2025.02.003
[26] Shiu KK, Jiang Y, Saunders M, et al. NEOPRISM-CRC: Neoadjuvant pembrolizumab stratified to tumour mutation burden for high – risk stage 2 or stage 3 deficient-MMR/MSI-high colorectal cancer. J Clin Oncol. 2024;42(17_suppl):LBA3504–4. doi: 10.1200/JCO.2024.42.17_suppl.LBA3504. DOI: https://doi.org/10.1200/JCO.2024.42.17_suppl.LBA3504
