Immunotherapy for microsatellite-stable colorectal cancer: overcoming resistance and exploring novel therapeutic strategies

Microsatellite-stable (MSS) colorectal cancer (CRC), comprising 85% to 95% of all CRC cases, represents a significant therapeutic challenge in the era of cancer immunotherapy. Unlike microsatellite instability-high tumors that demonstrate remarkable responses to immune checkpoint inhibitors, MSS CRC exhibits profound resistance due to low tumor mutational burden, minimal T-cell infiltration, and an immunosuppressive tumor microenvironment. This article reviews the current landscape of immunotherapy trials in MSS CRC, including the recently reported STELLAR-303 study, discusses emerging predictive biomarkers such as tumor mutational burden, Immunoscore Immune Checkpoint (Immunoscore-IC), and artificial intelligence-driven tools like Lunit SCOPE, and explores innovative strategies to overcome immune resistance, including next-generation anti-cytotoxic T-lymphocyte-associated protein-4 (anti-CTLA-4) antibodies, programmed cell death-ligand 1 (PD-L1)/interleukin-2 (IL-2) bispecific antibodies, CD47-targeting strategies, vaccines, and chimeric antigen receptor T (CAR-T) cell therapy. Understanding these evolving strategies is critical for advancing precision immunotherapy in this challenging patient population.