tumorsMalignant tumoursMalignant tumours2224-50572587-6813Rosoncoweb10.18027/2224-5057-2025-15-3s1-11-30tumors-1502Research ArticleСтатьиМеханизмы резистентности к иммунотерапии при MSI фенотипеhttps://orcid.org/0000-0001-5615-7806ФедянинМ. Ю.

Михаил Юрьевич Федянин

115478 Москва, Каширское шоссе, 23

105203 Москва, ул. Нижняя Первомайская, 70

108814, Москва, п. Коммунарка, ул. Сосенский стан, 8

fedianinmu@mail.ruФГБУ «Научный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава России; ФГБУ «Национальный медико-хирургический Центр им. Н. И. Пирогова» Минздрава России; ГБУЗ «Московский многопрофильный клинический центр «Коммунарка» Департамента здравоохранения г. Москвы»Russian Federation202530112025153s11130Copyright © Федянин М.Ю., 20252025Федянин М.Ю.Федянин М.Ю.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.malignanttumors.org/jour/article/view/1502

Цель: Обобщить современные представления о механизмах первичной и приобретённой резистентности к ингибиторам контрольных точек (ИКТ) при колоректальном раке (КРР) с dMMR / MSI.Материалы и методы: Нарративный обзор рецензируемой литературы и результатов клинических исследований ИКТ, включающий молекулярно-генетические, иммунологические, морфологические и микробиотические маркеры резистентности.Результаты: Резистентность при КРР с dMMR / MSI имеет многофакторную природу, к которой можно отнести дефекты антигенной презентации (β2‑микроглобулин, компоненты APM, HLA), нарушения сигнального пути IFN-γ / JAKSTAT, гиперактивность WNT / β-катенина, TGF-β-опосредованный сигналинг и ремоделирование стромы, а также особенности транскриптомных подтипов. Вклад микроокружения включает накопление Treg, MDSC, нейтрофилов и М2‑макрофагов, активацию фибробластов, ангиогенез и особенности метаболизма опухолевых клеток, а также экспансию дополнительных иммунных контрольных точек (LAG-3, TIM-3, TIGIT, IDO1), снижающих эффективность PD-1‑блокады. На уровне биомаркеров значимы: вариабельность TMB и степень выраженности MSI, результаты Immunoscore, морфологические признаки (например, наличие муцинозного компонента в опухоли), а также генетических причин развития MSI. Микробиота (в том числе F. nucleatum) ассоциирована с особенностями микрокружения опухоли и чувствительностью к ИКТ. Перспективные пути преодоления резистентности включают ко-блокаду PD-1 с CTLA-4 или LAG-3, сочетание с анти-VEGF-терапией и ингибиторами TGF-β, воздействие на миелоидные клетки, модуляцию микробиоты и новые таргетные подходы (например, ингибирование WRN).Заключение: Несмотря на высокую иммуногенность MSI-ассоциированного КРР, резистентность остаётся существенной клинической проблемой и требует стратификации по совокупности геномных, транскриптомных и иммунных признаков. Наиболее перспективной видится персонализированная комбинационная иммунотерапия на основе интегральной оценки антигенпрезентирующей функции, интерферонового сигналинга, микроокружения, морфологии, микробиоты и клинических признаков.

MSIdMMRколоректальный ракиммунотерапияингибиторы контрольных точекрезистентностьмикроокружение опухолиReferencesMuzny D.M., Bainbridge M.N., Chang K., et al. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487(7407):330–337. https://doi.org/10.1038/nature11252Muzny D.M., Bainbridge M.N., Chang K., et al. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487(7407):330–337. https://doi.org/10.1038/nature11252Venderbosch S., Nagtegaal I.D., Maughan T.S., et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: A pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res 2014;20(20):5322–5330. https://doi.org/10.1158/1078-0432.CCR-14-0800Venderbosch S., Nagtegaal I.D., Maughan T.S., et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: A pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res 2014;20(20):5322–5330. https://doi.org/10.1158/1078-0432.CCR-14-0800Herman J.G., Umar A., Polyak K., et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A 1998;95(12):6870–6875. https://doi.org/10.1073/pnas.95.12.6870Herman J.G., Umar A., Polyak K., et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A 1998;95(12):6870–6875. https://doi.org/10.1073/pnas.95.12.6870Sinicrope F.A., Sargent D.J. Molecular Pathways: Microsatellite Instability in Colorectal Cancer: Prognostic, Predictive, and Therapeutic Implications. Clin Cancer Res 2012;18(6):1506. https://doi.org/10.1158/1078-0432.CCR-11-1469Sinicrope F.A., Sargent D.J. Molecular Pathways: Microsatellite Instability in Colorectal Cancer: Prognostic, Predictive, and Therapeutic Implications. Clin Cancer Res 2012;18(6):1506. https://doi.org/10.1158/1078-0432.CCR-11-1469McGranahan N., Furness A.J.S., Rosenthal R., et al. Clonal neoantigens elicit t cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351(6280):1463–1469. https://doi.org/10.1126/science.aaf1490McGranahan N., Furness A.J.S., Rosenthal R., et al. Clonal neoantigens elicit t cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351(6280):1463–1469. https://doi.org/10.1126/science.aaf1490Mouw K.W., Goldberg M.S., Konstantinopoulos P. A, D’Andrea A.D. DNA damage and repair biomarkers of immunotherapy response. Cancer Discov 2017;7(7):675–693. https://doi.org/10.1158/2159-8290.CD-17-0226Mouw K.W., Goldberg M.S., Konstantinopoulos P. A, D’Andrea A.D. DNA damage and repair biomarkers of immunotherapy response. Cancer Discov 2017;7(7):675–693. https://doi.org/10.1158/2159-8290.CD-17-0226Germano G., Lamba S., Rospo G., et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 2017;552(7683):116–120. https://doi.org/10.1038/nature24673Germano G., Lamba S., Rospo G., et al. Inactivation of DNA repair triggers neoantigen generation and impairs tumour growth. Nature 2017;552(7683):116–120. https://doi.org/10.1038/nature24673Ou L., Zhang A., Cheng Y., Chen Y. The cGAS-STING pathway: a promising immunotherapy target. Front Immunol 2021;12:795048. https://doi.org/10.3389/fimmu.2021.795048Ou L., Zhang A., Cheng Y., Chen Y. The cGAS-STING pathway: a promising immunotherapy target. Front Immunol 2021;12:795048. https://doi.org/10.3389/fimmu.2021.795048Chang K., Taggart M.W., Reyes-Uribe L., et al. Immune profiling of premalignant lesions in patients with Lynch syndrome. JAMA Oncol 2018;4(8):1085–1092. https://doi.org/10.1001/jamaoncol.2018.1482Chang K., Taggart M.W., Reyes-Uribe L., et al. Immune profiling of premalignant lesions in patients with Lynch syndrome. JAMA Oncol 2018;4(8):1085–1092. https://doi.org/10.1001/jamaoncol.2018.1482Bohaumilitzky L., Kluck K., Hüneburg R., et al. The different immune profiles of normal colonic mucosa in cancer-free Lynch syndrome carriers and Lynch syndrome colorectal cancer patients. Gastroenterology 2021;162(3):907–919.e10. https://doi.org/10.1053/j.gastro.2021.11.029Bohaumilitzky L., Kluck K., Hüneburg R., et al. The different immune profiles of normal colonic mucosa in cancer-free Lynch syndrome carriers and Lynch syndrome colorectal cancer patients. Gastroenterology 2021;162(3):907–919.e10. https://doi.org/10.1053/j.gastro.2021.11.029Andre T., Shiu K.-K., Kim T.-W., et al. Final overall survival for the phase III KN177 study: Pembrolizumab versus chemotherapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). J Clin Oncol 2021;39(15_suppl):3500. https://doi.org/10.1200/JCO.2021.39.15_suppl.3500Andre T., Shiu K.-K., Kim T.-W., et al. Final overall survival for the phase III KN177 study: Pembrolizumab versus chemotherapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). J Clin Oncol 2021;39(15_suppl):3500. https://doi.org/10.1200/JCO.2021.39.15_suppl.3500Lenz H.J., Van Cutsem E., Luisa Limon M., et al. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study. J Clin Oncol 2022;40(2):161–170. https://doi.org/10.1200/JCO.21.02024Lenz H.J., Van Cutsem E., Luisa Limon M., et al. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study. J Clin Oncol 2022;40(2):161–170. https://doi.org/10.1200/JCO.21.02024Cohen R., Hain E., Buhard O., et al. Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite instability or mismatch repair deficiency status. JAMA Oncol 2019;5(5):551–555. https://doi.org/10.1001/jamaoncol.2018.4942Cohen R., Hain E., Buhard O., et al. Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite instability or mismatch repair deficiency status. JAMA Oncol 2019;5(5):551–555. https://doi.org/10.1001/jamaoncol.2018.4942Overman M.J., McDermott R., Leach J.L., 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;18(9):1182–1191. https://doi.org/10.1016/S1470-2045(17)30422-9Overman M.J., McDermott R., Leach J.L., 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;18(9):1182–1191. https://doi.org/10.1016/S1470-2045(17)30422-9Arai Y., Saito H., Ikeguchi M. Upregulation of TIM-3 and PD-1 on CD4 + and CD8 + T cells associated with dysfunction of cell-mediated immunity after colorectal cancer operation. Yonago Acta Med 2012;55(1):1–9Arai Y., Saito H., Ikeguchi M. Upregulation of TIM-3 and PD-1 on CD4 + and CD8 + T cells associated with dysfunction of cell-mediated immunity after colorectal cancer operation. Yonago Acta Med 2012;55(1):1–9Pelka K., Hofree M., Chen J.H., et al. Spatially organized multicellular immune hubs in human colorectal cancer. Cell 2021;184(18):4734–4752.e20. https://doi.org/10.1016/j.cell.2021.08.003Pelka K., Hofree M., Chen J.H., et al. Spatially organized multicellular immune hubs in human colorectal cancer. Cell 2021;184(18):4734–4752.e20. https://doi.org/10.1016/j.cell.2021.08.003Brand R.E., Dudley B., Karloski E., et al. Detection of DNA mismatch repair deficient crypts in random colonoscopic biopsies identifies Lynch syndrome patients. Fam Cancer 2020;19(2):169–175. https://doi.org/10.1007/s10689-020-00161-wBrand R.E., Dudley B., Karloski E., et al. Detection of DNA mismatch repair deficient crypts in random colonoscopic biopsies identifies Lynch syndrome patients. Fam Cancer 2020;19(2):169–175. https://doi.org/10.1007/s10689-020-00161-wDaniel B., Yost K.E., Hsiung S., et al. Divergent clonal differentiation trajectories of T cell exhaustion. Nat Immunol 2022;23(11):1614–1627. https://doi.org/10.1038/s41590-022-01337-5Daniel B., Yost K.E., Hsiung S., et al. Divergent clonal differentiation trajectories of T cell exhaustion. Nat Immunol 2022;23(11):1614–1627. https://doi.org/10.1038/s41590-022-01337-5Strauss L., Mahmoud M.A.A., Weaver J.D., et al. Targeted deletion of PD-1 in myeloid cells induces antitumor immunity. Sci Immunol 2020;5(44):eaay1863. https://doi.org/10.1126/sciimmunol.aay1863Strauss L., Mahmoud M.A.A., Weaver J.D., et al. Targeted deletion of PD-1 in myeloid cells induces antitumor immunity. Sci Immunol 2020;5(44):eaay1863. https://doi.org/10.1126/sciimmunol.aay1863Wang L., Sfakianos J.P., Beaumont K.G., et al. Myeloid cell-associated resistance to PD-1/PD-L1 blockade in urothelial cancer revealed through bulk and single-cell RNA sequencing. Clin Cancer Res 2021;27(15):4287–4300. https://doi.org/10.1158/1078-0432.CCR-20-4574Wang L., Sfakianos J.P., Beaumont K.G., et al. Myeloid cell-associated resistance to PD-1/PD-L1 blockade in urothelial cancer revealed through bulk and single-cell RNA sequencing. Clin Cancer Res 2021;27(15):4287–4300. https://doi.org/10.1158/1078-0432.CCR-20-4574Deryugina E.I., Quigley J.P. Tumor angiogenesis: MMP-mediated induction of intravasationand metastasis-sustaining neovasculature. Matrix Biol 2015;44–46:94–112. https://doi.org/10.1016/j.matbio.2015.04.004Deryugina E.I., Quigley J.P. Tumor angiogenesis: MMP-mediated induction of intravasationand metastasis-sustaining neovasculature. Matrix Biol 2015;44–46:94–112. https://doi.org/10.1016/j.matbio.2015.04.004Zhang J., Li S., Zhao Y., et al. Cancer-associated fibroblasts promote the migration and invasion of gastric cancer cells via activating IL-17a/JAK2/STAT3 signaling. Ann Transl Med 2020;8(14):877. https://doi.org/10.21037/atm-20-4843Zhang J., Li S., Zhao Y., et al. Cancer-associated fibroblasts promote the migration and invasion of gastric cancer cells via activating IL-17a/JAK2/STAT3 signaling. Ann Transl Med 2020;8(14):877. https://doi.org/10.21037/atm-20-4843Fontenot J.D., Rasmussen J.P., Williams L.M., et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 2005;22(3):329–341. https://doi.org/10.1016/j.immuni.2005.01.016Fontenot J.D., Rasmussen J.P., Williams L.M., et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 2005;22(3):329–341. https://doi.org/10.1016/j.immuni.2005.01.016Ohue Y., Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci 2019;110(8):2080–2089. https://doi.org/10.1111/cas.14069Ohue Y., Nishikawa H. Regulatory T (Treg) cells in cancer: Can Treg cells be a new therapeutic target? Cancer Sci 2019;110(8):2080–2089. https://doi.org/10.1111/cas.14069Vlad C., Kubelac P., Fetica B., et al. The prognostic value of FOXP3 + T regulatory cells in colorectal cancer. J Buon. 2015;20(1):114–119Vlad C., Kubelac P., Fetica B., et al. The prognostic value of FOXP3 + T regulatory cells in colorectal cancer. J Buon. 2015;20(1):114–119Waniczek D., Lorenc Z., Śnietura M., et al. Tumor-associated macrophages and regulatory T Cells infiltration and the clinical outcome in colorectal cancer. Arch Immunol Ther Exp 2017;65(5):445–454. https://doi.org/10.1007/s00005-017-0469-5Waniczek D., Lorenc Z., Śnietura M., et al. Tumor-associated macrophages and regulatory T Cells infiltration and the clinical outcome in colorectal cancer. Arch Immunol Ther Exp 2017;65(5):445–454. https://doi.org/10.1007/s00005-017-0469-5Lin Y.C., Mahalingam J., Chiang J.M., et al. Activated but not resting regulatory T cells accumulated in tumor microenvironment and correlated with tumor progression in patients with colorectal cancer. Int J Cancer 2013;132(6):1341–1350. https://doi.org/10.1002/ijc.27727Lin Y.C., Mahalingam J., Chiang J.M., et al. Activated but not resting regulatory T cells accumulated in tumor microenvironment and correlated with tumor progression in patients with colorectal cancer. Int J Cancer 2013;132(6):1341–1350. https://doi.org/10.1002/ijc.27727Saito T., Nishikawa H., Wada H., et al. Two FOXP3 + CD4 + T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med 2016;22(7):679–684. https://doi.org/10.1038/nm.4086Saito T., Nishikawa H., Wada H., et al. Two FOXP3 + CD4 + T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med 2016;22(7):679–684. https://doi.org/10.1038/nm.4086Llosa N.J., Cruise M., Tam A., et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 2015;5(1):43–51. https://doi.org/10.1158/2159-8290.CD-14-0863Llosa N.J., Cruise M., Tam A., et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 2015;5(1):43–51. https://doi.org/10.1158/2159-8290.CD-14-0863Sullivan K.M., Jiang X., Seo Y.D., et al. IL-10 blockade reactivates antitumor immunity in human colorectal cancer liver metastases. Cancer Res 2019;79(17):4489–4501. https://doi.org/10.1158/0008-5472.CAN-19-0814Sullivan K.M., Jiang X., Seo Y.D., et al. IL-10 blockade reactivates antitumor immunity in human colorectal cancer liver metastases. Cancer Res 2019;79(17):4489–4501. https://doi.org/10.1158/0008-5472.CAN-19-0814Bronte V., Brandau S., Chen S., et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 2016;7:12150. https://doi.org/10.1038/ncomms12150Bronte V., Brandau S., Chen S., et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 2016;7:12150. https://doi.org/10.1038/ncomms12150Bronte V., Zanovello P. Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 2005;5(8):641–654. https://doi.org/10.1038/nri1668Bronte V., Zanovello P. Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 2005;5(8):641–654. https://doi.org/10.1038/nri1668Geiger R., Rieckmann J.C., Wolf T., et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 2016;167(3):829–842.e13. https://doi.org/10.1016/j.cell.2016.09.031Geiger R., Rieckmann J.C., Wolf T., et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 2016;167(3):829–842.e13. https://doi.org/10.1016/j.cell.2016.09.031Huang B., Pan P.Y., Li Q., et al. Gr-1 + CD115 + immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res 2006;66(2):1123–1131. https://doi.org/10.1158/0008-5472.CAN-05-1299Huang B., Pan P.Y., Li Q., et al. Gr-1 + CD115 + immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. Cancer Res 2006;66(2):1123–1131. https://doi.org/10.1158/0008-5472.CAN-05-1299Angelova M., Charoentong P., Hackl H.L., et al. Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy. Genome Biol 2015;16:64. https://doi.org/10.1186/s13059-015-0620-6Angelova M., Charoentong P., Hackl H.L., et al. Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy. Genome Biol 2015;16:64. https://doi.org/10.1186/s13059-015-0620-6Cheng P., Corzo C.A., Luetteke N., et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 2008;205(10):2235–2249. https://doi.org/10.1084/jem.20080132Cheng P., Corzo C.A., Luetteke N., et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 2008;205(10):2235–2249. https://doi.org/10.1084/jem.20080132Chen X., Eksioglu E.A., Zhou J., et al. Induction of myelodysplasia by myeloid-derived suppressor cells. J Clin Invest 2013;123(11):4595–4611. https://doi.org/10.1172/JCI67580Chen X., Eksioglu E.A., Zhou J., et al. Induction of myelodysplasia by myeloid-derived suppressor cells. J Clin Invest 2013;123(11):4595–4611. https://doi.org/10.1172/JCI67580Yu Y., Blokhuis B., Derks Y., et al. Human mast cells promote colon cancer growth via bidirectional crosstalk: studies in 2D and 3D coculture models. Oncoimmunology 2018;7(10):e1504729. https://doi.org/10.1080/2162402X.2018.1504729Yu Y., Blokhuis B., Derks Y., et al. Human mast cells promote colon cancer growth via bidirectional crosstalk: studies in 2D and 3D coculture models. Oncoimmunology 2018;7(10):e1504729. https://doi.org/10.1080/2162402X.2018.1504729Sui Q., Zheng X., Cao C., et al. Inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer. Nat Commun 2022;13:7316. https://doi.org/10.1038/s41467-022-35096-6Sui Q., Zheng X., Cao C., et al. Inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer. Nat Commun 2022;13:7316. https://doi.org/10.1038/s41467-022-35096-6Wang T.T., Zhao Y.L., Peng L.S., et al. Tumour-activated neutrophils in gastric cancer foster immune suppression and disease progression through GM-CSF-PD-L1 pathway. Gut 2017;66(11):1900–1911. https://doi.org/10.1136/gut-jnl-2016-313075Wang T.T., Zhao Y.L., Peng L.S., et al. Tumour-activated neutrophils in gastric cancer foster immune suppression and disease progression through GM-CSF-PD-L1 pathway. Gut 2017;66(11):1900–1911. https://doi.org/10.1136/gut-jnl-2016-313075Giese M.A., Hind L.E., Hutenlocher A. Neutrophil plasticity in the tumor microenvironment. Blood 2019;133(20):2159–2167. https://doi.org/10.1182/blood-2019-01-7612Giese M.A., Hind L.E., Hutenlocher A. Neutrophil plasticity in the tumor microenvironment. Blood 2019;133(20):2159–2167. https://doi.org/10.1182/blood-2019-01-7612Zhang Y., Lee C., Geng S., Li L. Enhanced tumor immune surveillance through neutrophil reprogramming due to Tollip deficiency. JCI Insight 2019;4(16):e122939. https://doi.org/10.1172/jci.insight.122939Zhang Y., Lee C., Geng S., Li L. Enhanced tumor immune surveillance through neutrophil reprogramming due to Tollip deficiency. JCI Insight 2019;4(16):e122939. https://doi.org/10.1172/jci.insight.122939Anfray C., Ummarino A., Andón F.T., Allavena P. Current strategies to target tumor-associated macrophages to improve antitumor immune responses. Cells 2019;9(12):10046. https://doi.org/10.3390/cells91210046Anfray C., Ummarino A., Andón F.T., Allavena P. Current strategies to target tumor-associated macrophages to improve antitumor immune responses. Cells 2019;9(12):10046. https://doi.org/10.3390/cells91210046Chanmee T., Ontong P., Konno K., et al. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers 2014;6(3):1670–1690. https://doi.org/10.3390/cancers6031670Chanmee T., Ontong P., Konno K., et al. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers 2014;6(3):1670–1690. https://doi.org/10.3390/cancers6031670Mantovani A., Marchesi F., Malesci A., et al. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 2017;14(7):399–416. https://doi.org/10.1038/nrclinonc.2016.217Mantovani A., Marchesi F., Malesci A., et al. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 2017;14(7):399–416. https://doi.org/10.1038/nrclinonc.2016.217Martinez F.O., Gordon S. The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000Prime Rep 2014;6:13. https://doi.org/10.12703/P6-13Martinez F.O., Gordon S. The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000Prime Rep 2014;6:13. https://doi.org/10.12703/P6-13Narayanan S., Kawaguchi T., Peng X., et al. Tumor infiltrating lymphocytes and macrophages improve survival in microsatellite unstable colorectal cancer. Sci Rep 2019;9(1):13455. https://doi.org/10.1038/s41598-019-49770-0Narayanan S., Kawaguchi T., Peng X., et al. Tumor infiltrating lymphocytes and macrophages improve survival in microsatellite unstable colorectal cancer. Sci Rep 2019;9(1):13455. https://doi.org/10.1038/s41598-019-49770-0Erreni M., Mantovani A., Allavena P. Tumor-associated macrophages (TAM) and inflammation in colorectal cancer. Cancer Microenviron 2011;4(2):141–154. https://doi.org/10.1007/s12307-011-0072-0Erreni M., Mantovani A., Allavena P. Tumor-associated macrophages (TAM) and inflammation in colorectal cancer. Cancer Microenviron 2011;4(2):141–154. https://doi.org/10.1007/s12307-011-0072-0Korehisa S., Oki E., Iimori M., et al. Clinical significance of programmed cell death-ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability. Int J Cancer 2018;142(4):822–832. https://doi.org/10.1002/ijc.31027Korehisa S., Oki E., Iimori M., et al. Clinical significance of programmed cell death-ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability. Int J Cancer 2018;142(4):822–832. https://doi.org/10.1002/ijc.31027Georgoudaki A.M., Prokopec K.E., Boura V.F., et al. Reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis. Cell Rep 2016;15(9):2000–2011. https://doi.org/10.1016/j.cel-rep.2016.05.084Georgoudaki A.M., Prokopec K.E., Boura V.F., et al. Reprogramming tumor-associated macrophages by antibody targeting inhibits cancer progression and metastasis. Cell Rep 2016;15(9):2000–2011. https://doi.org/10.1016/j.cel-rep.2016.05.084Barrett R.L., Puré E. Cancer-associated fibroblasts and their influence on tumor immunity and immunotherapy. Elife 2020;9:e57243. https://doi.org/10.7554/eLife.57243Barrett R.L., Puré E. Cancer-associated fibroblasts and their influence on tumor immunity and immunotherapy. Elife 2020;9:e57243. https://doi.org/10.7554/eLife.57243Chakravarthy A., Khan L., Bensler N.P., et al. TGFβ-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat Commun 2018;9(1):4692. https://doi.org/10.1038/s41467-018-06999-3Chakravarthy A., Khan L., Bensler N.P., et al. TGFβ-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat Commun 2018;9(1):4692. https://doi.org/10.1038/s41467-018-06999-3Ford K., Hanley C.J., Mellone M., et al. NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumors. Cancer Res 2020;80(9):1846–1860. https://doi.org/10.1158/0008-5472.CAN-19-2995Ford K., Hanley C.J., Mellone M., et al. NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumors. Cancer Res 2020;80(9):1846–1860. https://doi.org/10.1158/0008-5472.CAN-19-2995Jenkins L., Jungwirth U., Avgustinova A., et al. Cancer-associated fibroblasts suppress CD8 + T-cell infiltration and confer resistance to immune-checkpoint blockade. Cancer Res 2022;82(16):2904–2917. https://doi.org/10.1158/0008-5472.CAN-21-3211Jenkins L., Jungwirth U., Avgustinova A., et al. Cancer-associated fibroblasts suppress CD8 + T-cell infiltration and confer resistance to immune-checkpoint blockade. Cancer Res 2022;82(16):2904–2917. https://doi.org/10.1158/0008-5472.CAN-21-3211Colegio O.R., Chu N.-Q., Szabo A.L., et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 2014;513(7519):559–563. https://doi.org/10.1038/nature13490Colegio O.R., Chu N.-Q., Szabo A.L., et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 2014;513(7519):559–563. https://doi.org/10.1038/nature13490Angelin A., Gil-de-Gomez L., Dahiya S., et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 2017;25(6):1282–1293.e7. https://doi.org/10.1016/j.cmet.2017.05.002Angelin A., Gil-de-Gomez L., Dahiya S., et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 2017;25(6):1282–1293.e7. https://doi.org/10.1016/j.cmet.2017.05.002Wang L., Fan J., Thompson L.F., et al. CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J Clin Invest 2011;121(6):2371–2382. https://doi.org/10.1172/JCI44794Wang L., Fan J., Thompson L.F., et al. CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J Clin Invest 2011;121(6):2371–2382. https://doi.org/10.1172/JCI44794Hammami A., Allard D., Allard B., Stagg J. Targeting the adenosine pathway for cancer immunotherapy. Semin Immunol 2019;42:101304. https://doi.org/10.1016/j.smim.2019.101304Hammami A., Allard D., Allard B., Stagg J. Targeting the adenosine pathway for cancer immunotherapy. Semin Immunol 2019;42:101304. https://doi.org/10.1016/j.smim.2019.101304Schreiber R.D., Old L.J., Smyth M.J. Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science 2011;331(6024):1565–1570. https://doi.org/10.1126/science.1203486Schreiber R.D., Old L.J., Smyth M.J. Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science 2011;331(6024):1565–1570. https://doi.org/10.1126/science.1203486Zaretsky J.M., Garcia-Diaz A., Shin D.S., et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 2016;375(9):819–829. https://doi.org/10.1056/NEJMoa1604958Zaretsky J.M., Garcia-Diaz A., Shin D.S., et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med 2016;375(9):819–829. https://doi.org/10.1056/NEJMoa1604958Bicknell D.C., Rowan A., Bodmer W.F. Beta 2-microglobulin gene mutations: A study of established colorectal cell lines and fresh tumors. Proc Natl Acad Sci U S A 1994;91(11):4751–4755. https://doi.org/10.1073/pnas.91.11.4751Bicknell D.C., Rowan A., Bodmer W.F. Beta 2-microglobulin gene mutations: A study of established colorectal cell lines and fresh tumors. Proc Natl Acad Sci U S A 1994;91(11):4751–4755. https://doi.org/10.1073/pnas.91.11.4751Wieczorek M., Abualrous E.T., Sticht J., et al. Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation. Front Immunol 2017;8:292. https://doi.org/10.3389/fimmu.2017.00292Wieczorek M., Abualrous E.T., Sticht J., et al. Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation. Front Immunol 2017;8:292. https://doi.org/10.3389/fimmu.2017.00292Chun E., Lavoie S., Michaud M., et al. CCL2 promotes colorectal carcinogenesis by enhancing polymorphonuclear myeloid-derived suppressor cell population and function. Cell Rep 2015;12:244–257. https://doi.org/10.1016/j.cel-rep.2015.06.024Chun E., Lavoie S., Michaud M., et al. CCL2 promotes colorectal carcinogenesis by enhancing polymorphonuclear myeloid-derived suppressor cell population and function. Cell Rep 2015;12:244–257. https://doi.org/10.1016/j.cel-rep.2015.06.024Clendenning M., Huang A., Jayasekara H., et al. Somatic mutations of the coding microsatellites within the beta-2-microglobulin gene in mismatch repair-deficient colorectal cancers and adenomas. Fam Cancer 2018;17:91–100. https://doi.org/10.1007/s10689-017-0013-yClendenning M., Huang A., Jayasekara H., et al. Somatic mutations of the coding microsatellites within the beta-2-microglobulin gene in mismatch repair-deficient colorectal cancers and adenomas. Fam Cancer 2018;17:91–100. https://doi.org/10.1007/s10689-017-0013-yDierssen J.W.F., de Miranda N.F., Ferrone S., et al. HNPCC versus sporadic microsatellite-unstable colon cancers follow different routes toward loss of HLA class I expression. BMC Cancer 2007;7:33. https://doi.org/10.1186/1471-2407-7-33Dierssen J.W.F., de Miranda N.F., Ferrone S., et al. HNPCC versus sporadic microsatellite-unstable colon cancers follow different routes toward loss of HLA class I expression. BMC Cancer 2007;7:33. https://doi.org/10.1186/1471-2407-7-33Ozcan M., Janikovits J., von Knebel Doeberitz M., Kloor M. Complex pattern of immune evasion in MSI colorectal cancer. Oncoimmunology 2018;7:e1445453. https://doi.org/10.1080/2162402X.2018.1445453Ozcan M., Janikovits J., von Knebel Doeberitz M., Kloor M. Complex pattern of immune evasion in MSI colorectal cancer. Oncoimmunology 2018;7:e1445453. https://doi.org/10.1080/2162402X.2018.1445453Sade-Feldman M., Jiao Y.J., Chen J.H., et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat Commun 2017;8:1136. https://doi.org/10.1038/s41467-017-01062-wSade-Feldman M., Jiao Y.J., Chen J.H., et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat Commun 2017;8:1136. https://doi.org/10.1038/s41467-017-01062-wGettinger S., Choi J., Hastings K., et al. Impaired HLA class i antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov 2017;7(12):1420–1435. https://doi.org/10.1158/2159-8290.CD-17-0593Gettinger S., Choi J., Hastings K., et al. Impaired HLA class i antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov 2017;7(12):1420–1435. https://doi.org/10.1158/2159-8290.CD-17-0593Gurjao C., Liu D., Hofree M., et al. Intrinsic resistance to immune checkpoint blockade in a mismatch repair–deficient colorectal cancer. Cancer Immunol Res 2019;7(8):1230–1236. https://doi.org/10.1158/2326-6066.CIR-18-0683Gurjao C., Liu D., Hofree M., et al. Intrinsic resistance to immune checkpoint blockade in a mismatch repair–deficient colorectal cancer. Cancer Immunol Res 2019;7(8):1230–1236. https://doi.org/10.1158/2326-6066.CIR-18-0683Middha S., Yaeger R., Shia J., et al. Majority of B2M-mutant and-deficient colorectal carcinomas achieve clinical benefit from immune checkpoint inhibitor therapy and are microsatellite instability-high. JCO Precis Oncol 2019;3:PO.18.00321. https://doi.org/10.1200/PO.18.00321Middha S., Yaeger R., Shia J., et al. Majority of B2M-mutant and-deficient colorectal carcinomas achieve clinical benefit from immune checkpoint inhibitor therapy and are microsatellite instability-high. JCO Precis Oncol 2019;3:PO.18.00321. https://doi.org/10.1200/PO.18.00321de Vries N.L., van de Haar J., Veninga V., et al. γδ T cells are effectors of immunotherapy in cancers with HLA class I defects. Nature 2023;613:743–750. https://doi.org/10.1038/s41586-022-05593-1de Vries N.L., van de Haar J., Veninga V., et al. γδ T cells are effectors of immunotherapy in cancers with HLA class I defects. Nature 2023;613:743–750. https://doi.org/10.1038/s41586-022-05593-1Germano G., Lu S., Rospo G., et al. CD4 T cell–dependent rejection of beta-2 microglobulin null mismatch repair-deficient tumors. Cancer Discov 2021;11(7):1844–1859. https://doi.org/10.1158/2159-8290.CD-20-0987Germano G., Lu S., Rospo G., et al. CD4 T cell–dependent rejection of beta-2 microglobulin null mismatch repair-deficient tumors. Cancer Discov 2021;11(7):1844–1859. https://doi.org/10.1158/2159-8290.CD-20-0987Salem M.E., Andre T., El-Refai S.M., et al. Impact of RAS mutations on immunologic characteristics of the tumor microenvironment (TME) in patients with microsatellite instability-high (MSI-H) or mismatch-repair–deficient (dMMR) colorectal cancer (CRC). Am Soc Clin Oncol 2022;40:3067. https://doi.org/10.1200/JCO.2022.40.16_sup-pl.3067Salem M.E., Andre T., El-Refai S.M., et al. Impact of RAS mutations on immunologic characteristics of the tumor microenvironment (TME) in patients with microsatellite instability-high (MSI-H) or mismatch-repair–deficient (dMMR) colorectal cancer (CRC). Am Soc Clin Oncol 2022;40:3067. https://doi.org/10.1200/JCO.2022.40.16_sup-pl.3067Liao W., Overman M.J., Boutin A.T., et al. KRAS-IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer. Cancer Cell 2019;35:559–572.e7. https://doi.org/10.1016/j.ccell.2019.02.008Liao W., Overman M.J., Boutin A.T., et al. KRAS-IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer. Cancer Cell 2019;35:559–572.e7. https://doi.org/10.1016/j.ccell.2019.02.008Becht E., de Reyniès A., Giraldo N.A., et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin Cancer Res 2016;22:4057–4066. https://doi.org/10.1158/1078-0432.CCR-15-2879Becht E., de Reyniès A., Giraldo N.A., et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin Cancer Res 2016;22:4057–4066. https://doi.org/10.1158/1078-0432.CCR-15-2879Lenz H.J., Lonardi S., Zagonel V., et al. Subgroup analyses of patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) treated with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line (1L) therapy: Two-year clinical update. Am Soc Clin Oncol 2021;39:58Lenz H.J., Lonardi S., Zagonel V., et al. Subgroup analyses of patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) treated with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line (1L) therapy: Two-year clinical update. Am Soc Clin Oncol 2021;39:58Shin D.S., Zaretsky J.M., Escuin-Ordinas H., et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov 2017;7(2):188–201. https://doi.org/10.1158/2159-8290.CD-16-0829Shin D.S., Zaretsky J.M., Escuin-Ordinas H., et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov 2017;7(2):188–201. https://doi.org/10.1158/2159-8290.CD-16-0829Sucker A., Zhao F., Pieper N., et al. Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions. Nat Commun 2017;8(1):15440. https://doi.org/10.1038/ncomms15440Sucker A., Zhao F., Pieper N., et al. Acquired IFNγ resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions. Nat Commun 2017;8(1):15440. https://doi.org/10.1038/ncomms15440Mathew D., Marmarelis M.E., Foley C., et al. Combined JAK inhibition and PD-1 immunotherapy for non–small cell lung cancer patients. Science 2024;384:1329. https://doi.org/10.1126/science.adf1329Mathew D., Marmarelis M.E., Foley C., et al. Combined JAK inhibition and PD-1 immunotherapy for non–small cell lung cancer patients. Science 2024;384:1329. https://doi.org/10.1126/science.adf1329Grasso C.S., Giannakis M., Wells D.K., et al. Genetic mechanisms of immune evasion in colorectal cancer. Cancer Discov 2018;8(6):730–749. https://doi.org/10.1158/2159-8290.CD-17-1327Grasso C.S., Giannakis M., Wells D.K., et al. Genetic mechanisms of immune evasion in colorectal cancer. Cancer Discov 2018;8(6):730–749. https://doi.org/10.1158/2159-8290.CD-17-1327Litchfield K., Reading J.L., Puttick C., et al. Meta-analysis of tumorand T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell 2021;184(3):596–614.e14. https://doi.org/10.1016/j.cell.2021.01.002Litchfield K., Reading J.L., Puttick C., et al. Meta-analysis of tumorand T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell 2021;184(3):596–614.e14. https://doi.org/10.1016/j.cell.2021.01.002Boukhaled G.M., Gadalla R., Elsaesser H.J., et al. Pre-encoded responsiveness to type I interferon in the peripheral immune system defines outcome of PD1 blockade therapy. Nat Immunol 2022;23(8):1273–1283. https://doi.org/10.1038/s41590-022-01262-7Boukhaled G.M., Gadalla R., Elsaesser H.J., et al. Pre-encoded responsiveness to type I interferon in the peripheral immune system defines outcome of PD1 blockade therapy. Nat Immunol 2022;23(8):1273–1283. https://doi.org/10.1038/s41590-022-01262-7Oshi M., Kawaguchi T., Yan L., et al. Immune cytolytic activity is associated with reduced intra-tumoral genetic heterogeneity and better clinical outcomes in triple negative breast cancer. Am J Cancer Res 2021;11(7):3628–3644.Oshi M., Kawaguchi T., Yan L., et al. Immune cytolytic activity is associated with reduced intra-tumoral genetic heterogeneity and better clinical outcomes in triple negative breast cancer. Am J Cancer Res 2021;11(7):3628–3644.Narayanan S., Kawaguchi T., Yan L., et al. Cytolytic activity score to assess anticancer immunity in colorectal cancer. Ann Surg Oncol 2018;25(8):2323–2331. https://doi.org/10.1245/s10434-018-6506-6Narayanan S., Kawaguchi T., Yan L., et al. Cytolytic activity score to assess anticancer immunity in colorectal cancer. Ann Surg Oncol 2018;25(8):2323–2331. https://doi.org/10.1245/s10434-018-6506-6Phillips S.M., Banerjea A., Feakins R., et al. Tumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic. Br J Surg 2004;91(4):469–475. https://doi.org/10.1002/bjs.4472Phillips S.M., Banerjea A., Feakins R., et al. Tumour-infiltrating lymphocytes in colorectal cancer with microsatellite instability are activated and cytotoxic. Br J Surg 2004;91(4):469–475. https://doi.org/10.1002/bjs.4472Ganesan S., Mehnert J. Biomarkers for response to immune checkpoint blockade. Annu Rev Cancer Biol 2020;4:331–351. https://doi.org/10.1146/annurev-cancerbio-030419-033604Ganesan S., Mehnert J. Biomarkers for response to immune checkpoint blockade. Annu Rev Cancer Biol 2020;4:331–351. https://doi.org/10.1146/annurev-cancerbio-030419-033604de Gooyer P.G.M., Chalabi M., van den Bulk J., et al. Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial. Nat Med 2024;30(11):3284–3290. https://doi.org/10.1038/s41591-024-03250-wde Gooyer P.G.M., Chalabi M., van den Bulk J., et al. Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial. Nat Med 2024;30(11):3284–3290. https://doi.org/10.1038/s41591-024-03250-wChalabi M., van den Bulk J., de Gooyer P., et al. Neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer. N Engl J Med 2024;390(21):1949–1958. https://doi.org/10.1056/NEJMoa2400634Chalabi M., van den Bulk J., de Gooyer P., et al. Neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer. N Engl J Med 2024;390(21):1949–1958. https://doi.org/10.1056/NEJMoa2400634Tauriello D.V.F., Palomo-Ponce S., Stork D., et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 2018;554(7693):538–543. https://doi.org/10.1038/nature25492Tauriello D.V.F., Palomo-Ponce S., Stork D., et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 2018;554(7693):538–543. https://doi.org/10.1038/nature25492Endo E., Okayama H., Saito K., et al. A TGFβ-Dependent Stromal Subset Underlies Immune Checkpoint Inhibitor Efficacy in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Colorectal Cancer. Mol Cancer Res 2020;18(9):1402–1413. https://doi.org/10.1158/1541-7786.MCR-20-0103Endo E., Okayama H., Saito K., et al. A TGFβ-Dependent Stromal Subset Underlies Immune Checkpoint Inhibitor Efficacy in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Colorectal Cancer. Mol Cancer Res 2020;18(9):1402–1413. https://doi.org/10.1158/1541-7786.MCR-20-0103Ravi R., Noonan K.A., Pham V., et al. Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat Commun 2018;9(1):741. https://doi.org/10.1038/s41467-017-02696-6Ravi R., Noonan K.A., Pham V., et al. Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat Commun 2018;9(1):741. https://doi.org/10.1038/s41467-017-02696-6Mariathasan S., Turley S.J., Nickles D., et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018;554(7693):544–548. https://doi.org/10.1038/nature25501Mariathasan S., Turley S.J., Nickles D., et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018;554(7693):544–548. https://doi.org/10.1038/nature25501Mizuno T., Cloyd J.M., Vicente D., et al. SMAD4 gene mutation predicts poor prognosis in patients undergoing resection for colorectal liver metastases. Eur J Surg Oncol 2018;44(5):684–692. https://doi.org/10.1016/j.ejso.2018.02.015Mizuno T., Cloyd J.M., Vicente D., et al. SMAD4 gene mutation predicts poor prognosis in patients undergoing resection for colorectal liver metastases. Eur J Surg Oncol 2018;44(5):684–692. https://doi.org/10.1016/j.ejso.2018.02.015Yoo S.Y., Lee J.A., Shin Y., et al. Clinicopathological characterization and prognostic implication of SMAD4 expression in colorectal carcinoma. J Pathol Transl Med 2019;53(5):289–297. https://doi.org/10.4132/jptm.2019.05.15Yoo S.Y., Lee J.A., Shin Y., et al. Clinicopathological characterization and prognostic implication of SMAD4 expression in colorectal carcinoma. J Pathol Transl Med 2019;53(5):289–297. https://doi.org/10.4132/jptm.2019.05.15Minn A.J., Wherry E.J. Combination cancer therapies with immune checkpoint blockade: convergence on interferon signaling. Cell 2016;165(2):272–275. https://doi.org/10.1016/j.cell.2016.03.031Minn A.J., Wherry E.J. Combination cancer therapies with immune checkpoint blockade: convergence on interferon signaling. Cell 2016;165(2):272–275. https://doi.org/10.1016/j.cell.2016.03.031Goldstein J., Tran B., Ensor J., et al. Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H). Ann Oncol 2014;25(5):1032–1038. https://doi.org/10.1093/annonc/mdu078Goldstein J., Tran B., Ensor J., et al. Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H). Ann Oncol 2014;25(5):1032–1038. https://doi.org/10.1093/annonc/mdu078Guinney J., Dienstmann R., Wang X., et al. The consensus molecular subtypes of colorectal cancer. Nat Med 2015;21(11):1350–1356. https://doi.org/10.1038/nm.3967Guinney J., Dienstmann R., Wang X., et al. The consensus molecular subtypes of colorectal cancer. Nat Med 2015;21(11):1350–1356. https://doi.org/10.1038/nm.3967Miyashita H., Bevins N.J., Thangathurai K., et al. The transcriptomic expression pattern of immune checkpoints shows heterogeneity between and within cancer types. Am J Cancer Res 2024;14(5):2240–2252. https://doi.org/10.62347/JRJP7877Miyashita H., Bevins N.J., Thangathurai K., et al. The transcriptomic expression pattern of immune checkpoints shows heterogeneity between and within cancer types. Am J Cancer Res 2024;14(5):2240–2252. https://doi.org/10.62347/JRJP7877Gallois C., Landi M., Taieb J., et al. Transcriptomic signatures of MSI-high metastatic colorectal cancer predict efficacy of immune checkpoint inhibitors. Clin Cancer Res 2023;29(18):3771–3778. https://doi.org/10.1158/1078-0432.CCR-22-3964Gallois C., Landi M., Taieb J., et al. Transcriptomic signatures of MSI-high metastatic colorectal cancer predict efficacy of immune checkpoint inhibitors. Clin Cancer Res 2023;29(18):3771–3778. https://doi.org/10.1158/1078-0432.CCR-22-3964Esposito A., Agostini A., Quero G., et al. Colorectal cancer patients-derived immunity-organoid platform unveils cancer-specific tissue markers associated with immunotherapy resistance. Cell Death Dis 2024;15:123. https://doi.org/10.1038/s41419-024-07266-5Esposito A., Agostini A., Quero G., et al. Colorectal cancer patients-derived immunity-organoid platform unveils cancer-specific tissue markers associated with immunotherapy resistance. Cell Death Dis 2024;15:123. https://doi.org/10.1038/s41419-024-07266-5Schrock A.B., Ouyang C., Sandhu J., et al. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann Oncol 2019;30(7):1096–1103. https://doi.org/10.1093/annonc/mdz134Schrock A.B., Ouyang C., Sandhu J., et al. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann Oncol 2019;30(7):1096–1103. https://doi.org/10.1093/annonc/mdz134Elez M.E., Mulet-Margalef N., Sanso M., et al. A Comprehensive Biomarker Analysis of Microsatellite Unstable/ Mismatch Repair Deficient Colorectal Cancer Cohort Treated with Immunotherapy. Int J Mol Sci 2022;24(1):118. https://doi:10.3390/ijms24010118Elez M.E., Mulet-Margalef N., Sanso M., et al. A Comprehensive Biomarker Analysis of Microsatellite Unstable/ Mismatch Repair Deficient Colorectal Cancer Cohort Treated with Immunotherapy. Int J Mol Sci 2022;24(1):118. https://doi:10.3390/ijms24010118Shen J., Ju Z., Zhao W., et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med 2018;4(5):556–562. https://doi.org/10.1038/s41591-018-0012-zShen J., Ju Z., Zhao W., et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med 2018;4(5):556–562. https://doi.org/10.1038/s41591-018-0012-zPan D., Kobayashi A., Jiang P., et al. A major chromatin regulator determines resistance of tumor cells to T cell–mediated killing. Science 2018;359(6377):770–775. https://doi.org/10.1126/science.aao1710Pan D., Kobayashi A., Jiang P., et al. A major chromatin regulator determines resistance of tumor cells to T cell–mediated killing. Science 2018;359(6377):770–775. https://doi.org/10.1126/science.aao1710Collins N.B., Al Abosy R., Miller B.C., et al. PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment. J Immunother Cancer 2022;10(3):e003402. https://doi.org/10.1136/jitc-2021-003402Collins N.B., Al Abosy R., Miller B.C., et al. PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment. J Immunother Cancer 2022;10(3):e003402. https://doi.org/10.1136/jitc-2021-003402Chida K., Parikh A.R., Futreal P.A., et al. A low tumor mutational burden and PTEN mutations are predictors of a negative response to PD-1 blockade in MSI-H/dMMR gastrointestinal tumors. Clin Cancer Res 2021;27(13):3714–3724. https://doi.org/10.1158/1078-0432.CCR-21-0401Chida K., Parikh A.R., Futreal P.A., et al. A low tumor mutational burden and PTEN mutations are predictors of a negative response to PD-1 blockade in MSI-H/dMMR gastrointestinal tumors. Clin Cancer Res 2021;27(13):3714–3724. https://doi.org/10.1158/1078-0432.CCR-21-0401Wang Z., Zhang Q., Qi C., et al. Combination of AKT1 and CDH1 mutations predicts primary resistance to immunotherapy in dMMR/MSI-H gastrointestinal cancer. J Immunother Cancer 2022;10:e004703. https://doi.org/10.1136/jitc-2021-004703Wang Z., Zhang Q., Qi C., et al. Combination of AKT1 and CDH1 mutations predicts primary resistance to immunotherapy in dMMR/MSI-H gastrointestinal cancer. J Immunother Cancer 2022;10:e004703. https://doi.org/10.1136/jitc-2021-004703Wang Z., Li J., Li W., et al. Mutations of PI3K–AKT–mTOR pathway as predictors for immune cell infiltration and immunotherapy efficacy in dMMR/MSI-H gastric adenocarcinoma. BMC Med 2022;20(1):1–15. https://doi.org/10.1186/s12916-022-02298-2Wang Z., Li J., Li W., et al. Mutations of PI3K–AKT–mTOR pathway as predictors for immune cell infiltration and immunotherapy efficacy in dMMR/MSI-H gastric adenocarcinoma. BMC Med 2022;20(1):1–15. https://doi.org/10.1186/s12916-022-02298-2Alsaafeen B.H., Ali B.R., Elkord E. Resistance mechanisms to immune checkpoint inhibitors: updated insights. Mol Cancer 2025;24(1):20. https://doi.org/10.1186/s12943-024-02212-7Alsaafeen B.H., Ali B.R., Elkord E. Resistance mechanisms to immune checkpoint inhibitors: updated insights. Mol Cancer 2025;24(1):20. https://doi.org/10.1186/s12943-024-02212-7Kim J.H., Park H.E., Cho N.Y., et al. Characterisation of PD-L1-positive subsets of microsatellite-unstable colorectalcancers. Br J Cancer 2016;115(4):490–6. https://doi.org/10.1038/bjc.2016.211Kim J.H., Park H.E., Cho N.Y., et al. Characterisation of PD-L1-positive subsets of microsatellite-unstable colorectalcancers. Br J Cancer 2016;115(4):490–6. https://doi.org/10.1038/bjc.2016.211Hu H., Kang L., Zhang J., et al. Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2022;7(1):38–48. https://doi.org/10.1016/S2468-1253(21)00348-4Hu H., Kang L., Zhang J., et al. Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2022;7(1):38–48. https://doi.org/10.1016/S2468-1253(21)00348-4Guo Z., Hong D., Wei Y., et al. Differential response to immunotherapy in different lesions of MSI-H double primary colorectal cancer: a case report and literature review. AME Case Rep 2024;9:17. https://doi.org/10.21037/acr-24-137Guo Z., Hong D., Wei Y., et al. Differential response to immunotherapy in different lesions of MSI-H double primary colorectal cancer: a case report and literature review. AME Case Rep 2024;9:17. https://doi.org/10.21037/acr-24-137Dalerba P., Sahoo D., Paik S., et al. CDX2 as a prognostic biomarker in stage II and stage III colon cancer. N Engl J Med 2016;374(3):211–222. https://doi.org/10.1056/NEJMoa1506597Dalerba P., Sahoo D., Paik S., et al. CDX2 as a prognostic biomarker in stage II and stage III colon cancer. N Engl J Med 2016;374(3):211–222. https://doi.org/10.1056/NEJMoa1506597Aasebø K., Dragomir A., Sundström M., et al. CDX2: A prognostic marker in metastatic colorectal cancer defining a better BRAF mutated and a worse KRAS mutated subgroup. Front Oncol 2020;10:8. https://doi.org/10.3389/fonc.2020.00008Aasebø K., Dragomir A., Sundström M., et al. CDX2: A prognostic marker in metastatic colorectal cancer defining a better BRAF mutated and a worse KRAS mutated subgroup. Front Oncol 2020;10:8. https://doi.org/10.3389/fonc.2020.00008Aimola V., Fanni D., Gerosa C., et al. Balance between the stem cell marker CD44 and CDX2 expression in colorectal cancer. Ann Res Oncol 2022;2(2):160–166. https://doi.org/10.48286/aro.2022.43Aimola V., Fanni D., Gerosa C., et al. Balance between the stem cell marker CD44 and CDX2 expression in colorectal cancer. Ann Res Oncol 2022;2(2):160–166. https://doi.org/10.48286/aro.2022.43Ziranu P., Pretta A., Pozzari M., et al. CDX-2 expression correlates with clinical outcomes in MSI-H metastatic colorectal cancer patients receiving immune checkpoint inhibitors. Sci Rep 2023;13(1):4397. https://doi.org/10.1038/s41598-023-31538-3Ziranu P., Pretta A., Pozzari M., et al. CDX-2 expression correlates with clinical outcomes in MSI-H metastatic colorectal cancer patients receiving immune checkpoint inhibitors. Sci Rep 2023;13(1):4397. https://doi.org/10.1038/s41598-023-31538-3Jaffrelot M., Jean B., Leduc C., et al. An unusual phenotype occurs in 15% of mismatch repair-deficient tumors and is associated with non-colorectal cancers and genetic syndromes. Mod Pathol 2022;35(3):427–437. https://doi.org/10.1038/s41379-021-00942-8Jaffrelot M., Jean B., Leduc C., et al. An unusual phenotype occurs in 15% of mismatch repair-deficient tumors and is associated with non-colorectal cancers and genetic syndromes. Mod Pathol 2022;35(3):427–437. https://doi.org/10.1038/s41379-021-00942-8Ratovomanana T., Nicolle R., Cohen R., et al. Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability. Ann Oncol 2023;34(8):703–713. https://doi.org/10.1016/j.annonc.2023.04.002Ratovomanana T., Nicolle R., Cohen R., et al. Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability. Ann Oncol 2023;34(8):703–713. https://doi.org/10.1016/j.annonc.2023.04.002Castellarin M., Warren R.L., Freeman J.D., et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res 2012;22(2):299–306. https://doi.org/10.1101/gr.126516.111Castellarin M., Warren R.L., Freeman J.D., et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res 2012;22(2):299–306. https://doi.org/10.1101/gr.126516.111Temraz S., Nassar F., Nasr R., et al. Gut microbiome: A promising biomarker for immunotherapy in colorectal cancer. Int J Mol Sci 2019;20(21):4155. https://doi.org/10.3390/ijms20174155Temraz S., Nassar F., Nasr R., et al. Gut microbiome: A promising biomarker for immunotherapy in colorectal cancer. Int J Mol Sci 2019;20(21):4155. https://doi.org/10.3390/ijms20174155Hamada T., Zhang X., Mima K., et al. Fusobacterium nucleatum in colorectal cancer relates to immune response differentially by tumor microsatellite instability status. Cancer Immunol Res 2018;6(11):1327–1336. https://doi.org/10.1158/2326-6066.CIR-18-0174Hamada T., Zhang X., Mima K., et al. Fusobacterium nucleatum in colorectal cancer relates to immune response differentially by tumor microsatellite instability status. Cancer Immunol Res 2018;6(11):1327–1336. https://doi.org/10.1158/2326-6066.CIR-18-0174Sivan A., Corrales L., Hubert N., et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015;350(6264):1084–1089. https://doi.org/10.1126/science.aac4255Sivan A., Corrales L., Hubert N., et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015;350(6264):1084–1089. https://doi.org/10.1126/science.aac4255Frankel A.E., Coughlin L.A., Kim J., et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia 2017;19(10):848–855. https://doi.org/10.1016/j.neo.2017.08.004Frankel A.E., Coughlin L.A., Kim J., et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia 2017;19(10):848–855. https://doi.org/10.1016/j.neo.2017.08.004Zhuo Q., Yu B., Zhou J., et al. Lysates of Lactobacillus acidophilus combined with CTLA-4-blocking antibodies enhance antitumor immunity in a mouse colon cancer model. Sci Rep 2019;9(1):20128. https://doi.org/10.1038/s41598-019-56661-yZhuo Q., Yu B., Zhou J., et al. Lysates of Lactobacillus acidophilus combined with CTLA-4-blocking antibodies enhance antitumor immunity in a mouse colon cancer model. Sci Rep 2019;9(1):20128. https://doi.org/10.1038/s41598-019-56661-yCheng S., Han Z., Dai D., et al. Multi-omics of the gut microbial ecosystem in patients with microsatellite-instability-high gastrointestinal cancer resistant to immunotherapy. Gut Microbes 2024;5(1):101355. https://doi.org/10.1016/j.xcrm.2023.101355Cheng S., Han Z., Dai D., et al. Multi-omics of the gut microbial ecosystem in patients with microsatellite-instability-high gastrointestinal cancer resistant to immunotherapy. Gut Microbes 2024;5(1):101355. https://doi.org/10.1016/j.xcrm.2023.101355Davar D., Dzutsev A.K., McCulloch J.A., et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science 2021;371(6529):595–602. https://doi.org/10.1126/science.abf3363Davar D., Dzutsev A.K., McCulloch J.A., et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science 2021;371(6529):595–602. https://doi.org/10.1126/science.abf3363Ogino S., Galon J., Fuchs C.S., Dranoff G. Cancer immunology—analysis of host and tumor factors for personalized medicine. Nat Rev Clin Oncol 2011;8(12):711–719. https://doi.org/10.1038/nrclinonc.2011.122Ogino S., Galon J., Fuchs C.S., Dranoff G. Cancer immunology—analysis of host and tumor factors for personalized medicine. Nat Rev Clin Oncol 2011;8(12):711–719. https://doi.org/10.1038/nrclinonc.2011.122Galon J., Costes A., Sanchez-Cabo F., et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313(5795):1960–4. https://doi.org/10.1126/science.1129139Galon J., Costes A., Sanchez-Cabo F., et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006;313(5795):1960–4. https://doi.org/10.1126/science.1129139Galon J., Pagès F., Marincola F.M., et al. Cancer classification using the Immunoscore: A worldwide task force. J Transl Med 2012;10:205. https://doi.org/10.1186/1479-5876-10-205Galon J., Pagès F., Marincola F.M., et al. Cancer classification using the Immunoscore: A worldwide task force. J Transl Med 2012;10:205. https://doi.org/10.1186/1479-5876-10-205Wirta E.V., Seppälä T., Friman M., et al. Immunoscore in mismatch repair-proficient and -deficient colon cancer. J Pathol Clin Res. 2017;3(3):203–213. https://doi.org/10.1002/cjp2.71Wirta E.V., Seppälä T., Friman M., et al. Immunoscore in mismatch repair-proficient and -deficient colon cancer. J Pathol Clin Res. 2017;3(3):203–213. https://doi.org/10.1002/cjp2.71Chakrabarti S., Huebner L.J., Finnes H.D., et al. Intratumoral CD3 + and CD8 + T-Cell densities in patients with DNA mismatch repair–deficient metastatic colorectal cancer receiving programmed cell death-1 blockade. JCO Precis Oncol 2019;3:1–7. https://doi.org/10.1200/PO.19.00055Chakrabarti S., Huebner L.J., Finnes H.D., et al. Intratumoral CD3 + and CD8 + T-Cell densities in patients with DNA mismatch repair–deficient metastatic colorectal cancer receiving programmed cell death-1 blockade. JCO Precis Oncol 2019;3:1–7. https://doi.org/10.1200/PO.19.00055Tian S., Wang F., Zhang R., Chen G. Global Pattern of CD8 + T-Cell infiltration and exhaustion in colorectal cancer predicts cancer immunotherapy response. Front Pharmacol 2021;12:715721. https://doi.org/10.3389/fphar.2021.715721Tian S., Wang F., Zhang R., Chen G. Global Pattern of CD8 + T-Cell infiltration and exhaustion in colorectal cancer predicts cancer immunotherapy response. Front Pharmacol 2021;12:715721. https://doi.org/10.3389/fphar.2021.715721Ryan A.F., Nasamran C.A., Pak K., et al. Single-Cell transcriptomes reveal a complex cellular landscape in the middle ear and differential capacities for acute response to infection. Front Genet 2020;11:358. https://doi.org/10.3389/fgene.2020.00358Ryan A.F., Nasamran C.A., Pak K., et al. Single-Cell transcriptomes reveal a complex cellular landscape in the middle ear and differential capacities for acute response to infection. Front Genet 2020;11:358. https://doi.org/10.3389/fgene.2020.00358Huang Y.H., Kim B.Y.S., Chan C.K., et al. Improving immune-vascular crosstalk for cancer immunotherapy. Nat Rev Immunol 2018;18(3):195–203. https://doi.org/10.1038/nri.2017.145Huang Y.H., Kim B.Y.S., Chan C.K., et al. Improving immune-vascular crosstalk for cancer immunotherapy. Nat Rev Immunol 2018;18(3):195–203. https://doi.org/10.1038/nri.2017.145Fukumura D., Kloepper J., Amoozgar Z., et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 2018;15(5):325–40. https://doi.org/10.1038/nrclinonc.2018.29Fukumura D., Kloepper J., Amoozgar Z., et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 2018;15(5):325–40. https://doi.org/10.1038/nrclinonc.2018.29Chen M.F., Wang Z.H., Liu Z.M., et al. The optimal therapy after progression on immune checkpoint inhibitors in MSI metastatic gastrointestinal cancer patients: a multicenter retrospective cohort study. Cancers (Basel) 2022;14(20):5158. https://doi.org/10.3390/cancers14205158Chen M.F., Wang Z.H., Liu Z.M., et al. The optimal therapy after progression on immune checkpoint inhibitors in MSI metastatic gastrointestinal cancer patients: a multicenter retrospective cohort study. Cancers (Basel) 2022;14(20):5158. https://doi.org/10.3390/cancers14205158Li H.L., Ning T., Zhang L., et al. A single center phase 2 study of anti-PD-1 antibody plus bevacizumab and FOLFIRI as second-line treatment for patients with MSI-H metastatic colorectal cancer. J Clin Oncol 2022;40(16_suppl):e15541. https://doi.org/10.1200/JCO.2022.40.16_suppl.e15541Li H.L., Ning T., Zhang L., et al. A single center phase 2 study of anti-PD-1 antibody plus bevacizumab and FOLFIRI as second-line treatment for patients with MSI-H metastatic colorectal cancer. J Clin Oncol 2022;40(16_suppl):e15541. https://doi.org/10.1200/JCO.2022.40.16_suppl.e15541Huang Q., Zheng X., Xu W. Case Report: A long-term response of immunotherapy combined with anti-angiogenesis therapy in a patient with dMMR metastatic colorectal cancer after ICI failure. Front Oncol 2025;15:1553380. https://doi.org/10.3389/fonc.2025.1553380Huang Q., Zheng X., Xu W. Case Report: A long-term response of immunotherapy combined with anti-angiogenesis therapy in a patient with dMMR metastatic colorectal cancer after ICI failure. Front Oncol 2025;15:1553380. https://doi.org/10.3389/fonc.2025.1553380Moreira L., Balaguer F., Lindor N., et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA 2012;308(15):1555–1565. https://doi.org/10.1001/jama.2012.13088Moreira L., Balaguer F., Lindor N., et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA 2012;308(15):1555–1565. https://doi.org/10.1001/jama.2012.13088Le D.T., Durham J.N., Smith K.N., et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357(6349):409–413. https://doi.org/10.1126/science.aan6733Le D.T., Durham J.N., Smith K.N., et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357(6349):409–413. https://doi.org/10.1126/science.aan6733Overman M.J., Lonardi S., Wong K.Y.M., et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018;36(8):773–779. https://doi.org/10.1200/JCO.2017.76.9901Overman M.J., Lonardi S., Wong K.Y.M., et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol 2018;36(8):773–779. https://doi.org/10.1200/JCO.2017.76.9901Chalabi M., Verschoor Y., van den Berg J., et al. Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study. Ann Oncol 2022;33:S1389. https://doi.org/10.1016/j.annonc.2022.08.016Chalabi M., Verschoor Y., van den Berg J., et al. Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study. Ann Oncol 2022;33:S1389. https://doi.org/10.1016/j.annonc.2022.08.016Maoz A., Biller L., Giannakis M., et al. Causes of Death among individuals with Lynch syndrome in the immunotherapy era. JCO Precis Oncol 2025 Oct;9:e2500700. https://doi.org/10.1200/PO-25-00700Maoz A., Biller L., Giannakis M., et al. Causes of Death among individuals with Lynch syndrome in the immunotherapy era. JCO Precis Oncol 2025 Oct;9:e2500700. https://doi.org/10.1200/PO-25-00700Randrian V., Artz O., Mohammad M., et al. Gene-specific outcomes in patients with Lynch syndrome treated by immune checkpoint blockade for advanced cancer. J Clin Oncol 2025;43(16_suppl):10504. https://doi.org/10.1200/JCO.2025.43.16_suppl.10504Randrian V., Artz O., Mohammad M., et al. Gene-specific outcomes in patients with Lynch syndrome treated by immune checkpoint blockade for advanced cancer. J Clin Oncol 2025;43(16_suppl):10504. https://doi.org/10.1200/JCO.2025.43.16_suppl.10504Khushman M.M., Chuk M.K., Kavan P., et al. Differential responses to immune checkpoint inhibitors are governed by diverse mismatch repair gene alterations. Clin Cancer Res 2024;30(9):1906–1915. https://doi.org/10.1158/1078-0432.CCR-23-3115Khushman M.M., Chuk M.K., Kavan P., et al. Differential responses to immune checkpoint inhibitors are governed by diverse mismatch repair gene alterations. Clin Cancer Res 2024;30(9):1906–1915. https://doi.org/10.1158/1078-0432.CCR-23-3115Alouani E.L., Mercier M., Flecchia C., et al. Efficacy of immunotherapy in gastro-intestinal (GI) tumors with mismatch repair deficient (MMRd) unusual phenotype. Ann Oncol 2024;35(Suppl 2):S272. https://doi.org/10.1016/j.annonc.2024.04.163Alouani E.L., Mercier M., Flecchia C., et al. Efficacy of immunotherapy in gastro-intestinal (GI) tumors with mismatch repair deficient (MMRd) unusual phenotype. Ann Oncol 2024;35(Suppl 2):S272. https://doi.org/10.1016/j.annonc.2024.04.163Randrian V., Sweeney K., Alouani E., et al. The mechanism of mismatch repair deficiency (MMRd) informs survival outcomes derived from immune checkpoint blockade (ICB) across MMRd solid tumors. Ann Oncol 2025;36(Suppl 2):S246-S247. https://doi.org/10.1016/j.annonc.2025.08.545Randrian V., Sweeney K., Alouani E., et al. The mechanism of mismatch repair deficiency (MMRd) informs survival outcomes derived from immune checkpoint blockade (ICB) across MMRd solid tumors. Ann Oncol 2025;36(Suppl 2):S246-S247. https://doi.org/10.1016/j.annonc.2025.08.545Bellone S., Roque D.M., Siegel E.R., et al. A phase 2 evaluation of pembrolizumab for recurrent lynch-like versus sporadic endometrial cancers with microsatellite instability. Cancer 2021;28:1206–18. https://doi.org/10.1002/cncr.34025Bellone S., Roque D.M., Siegel E.R., et al. A phase 2 evaluation of pembrolizumab for recurrent lynch-like versus sporadic endometrial cancers with microsatellite instability. Cancer 2021;28:1206–18. https://doi.org/10.1002/cncr.34025Chow R.D., Michaels T., Bellone S., et al. Distinct mechanisms of mismatch repair deficiency delineate two modes of response to PD-1 immunotherapy in endometrial carcinoma. Cancer Discov 2022;13:CD–220686. https://doi.org/10.1158/2159-8290.CD-22-0686Chow R.D., Michaels T., Bellone S., et al. Distinct mechanisms of mismatch repair deficiency delineate two modes of response to PD-1 immunotherapy in endometrial carcinoma. Cancer Discov 2022;13:CD–220686. https://doi.org/10.1158/2159-8290.CD-22-0686Das S., Chae Y.K., Giles F.J., et al. Immunotherapy after immunotherapy: response rescue in a patient with microsatellite instability-high colorectal cancer post-pembrolizumab. JCO Precision Oncology 2020;4:454–460. https://doi.org/10.1200/PO.20.00105Das S., Chae Y.K., Giles F.J., et al. Immunotherapy after immunotherapy: response rescue in a patient with microsatellite instability-high colorectal cancer post-pembrolizumab. JCO Precision Oncology 2020;4:454–460. https://doi.org/10.1200/PO.20.00105Picco G., Mena E., Arsenian-Henriksson M., et al. Werner helicase is a synthetic-lethal vulnerability in mismatch repair-deficient colorectal cancer refractory to targeted therapies, chemotherapy, and immunotherapy. Cancer Discov 2021;11(8):1862–1877. https://doi.org/10.1158/2159-8290.CD-20-1689Picco G., Mena E., Arsenian-Henriksson M., et al. Werner helicase is a synthetic-lethal vulnerability in mismatch repair-deficient colorectal cancer refractory to targeted therapies, chemotherapy, and immunotherapy. Cancer Discov 2021;11(8):1862–1877. https://doi.org/10.1158/2159-8290.CD-20-1689Yap T.A., Cook N., Fontana E., et al. Abstract CT016: First-in-human (FIH) phase 1 trial of the oral first-in-class covalent Werner helicase (WRN) inhibitor RO7589831 in patients with microsatellite instable (MSI) and/or mismatch repair deficient (dMMR) advanced solid tumors. Cancer Res 2025;85(8_Supplement_2):CT016. https://doi.org/10.1158/1538-7445.AM2025-CT016Yap T.A., Cook N., Fontana E., et al. Abstract CT016: First-in-human (FIH) phase 1 trial of the oral first-in-class covalent Werner helicase (WRN) inhibitor RO7589831 in patients with microsatellite instable (MSI) and/or mismatch repair deficient (dMMR) advanced solid tumors. Cancer Res 2025;85(8_Supplement_2):CT016. https://doi.org/10.1158/1538-7445.AM2025-CT016Foote M.B.B., Li J., Tan D.S., et al. 925MO First-in-human phase I/Ib study of the oral Werner (WRN) helicase inhibitor HRO761 in patients (pts) with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors: Interim safety and efficacy analysis from HRO761 single agent dose escalation. Ann Oncol 2025;36(Suppl_2):S605-S606. https://doi.org/10.1016/j.annonc.2025.08.1494.Foote M.B.B., Li J., Tan D.S., et al. 925MO First-in-human phase I/Ib study of the oral Werner (WRN) helicase inhibitor HRO761 in patients (pts) with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors: Interim safety and efficacy analysis from HRO761 single agent dose escalation. Ann Oncol 2025;36(Suppl_2):S605-S606. https://doi.org/10.1016/j.annonc.2025.08.1494.

The authors declare that there are no conflicts of interest present.