Combination immunotherapy for colorectal cancer: Clinical applications, rationale, challenges, and future perspectives

Colorectal cancer (CRC) is a leading cause of cancer-related mortality. Although immunotherapy has demonstrated remarkable efficacy in deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) tumors, most proficient mismatch repair (pMMR)/microsatellite stability (MSS)/microsatellite instability-low (MSI-L) patients derive limited benefit. Combination strategies-including immune checkpoint inhibitors (ICIs), chemotherapy, targeted therapy, and radiotherapy-offer promise for overcoming resistance. This review examines recent clinical advances in combination immunotherapy for CRC, with a focus on tumor microenvironment (TME) modulation and predictive biomarkers. By bridging preclinical insights and clinical applications, we aim to facilitate the optimization of therapeutic strategies and extend the benefits of immunotherapy across CRC subtypes.