Biomarkers and future directions for immunotherapy in microsatellite-stable colorectal cancer: a systematic review

The mechanisms of resistance to immune checkpoint inhibitors (ICIs) in microsatellite-stable (MSS) colorectal cancer (CRC) have 3 interconnected levels, which provide information to guide different biomarker strategies. There is a critical clinical need, as objective response rates continue to be < 10%. We suggest a biomarker stratification model on the basis of clinical actionability. POLE/POLD1 mutations, recommended by the NCCN Clinical Practice Guidelines in Oncology for Colon Cancer (Version 1.2025), represent true genomic "hard" indicators. While the benefit of ICI-containing combination regimens was predicted by the Immunoscore-IC in the AtezoTRIBE trial, the ANICCA-class II study recently questioned the value of anti-PD-1 monotherapy. Defects in homologous recombination repair HRR), ctDNA kinetics and subtyping of CMS1 show promise but need to be prospectively validated. TMB, however, has shown no consistent value as a single biomarker, and MSIs, such as transcriptomic signatures or PD-L1 combined positive scores, have not been proven to be useful. Future prospects involve multiomics algorithms that integrate immune profiling and stromal determinants, liver-directed sensitizing approaches and serial ctDNA monitoring of acquired resistance as viable strategies for further patient selection. These data collectively pave the way toward moving away from the "cold tumor" paradigm and toward dynamic, host-integrated testing for precision immunotherapy in MSS CRC.