Systematic review maps biomarkers for immunotherapy in microsatellite-stable colorectal cancer

Immune checkpoint inhibitors have transformed the treatment of microsatellite instability-high colorectal cancer, but patients whose tumors are microsatellite-stable (MSS) rarely benefit, with objective response rates continuing to fall below 10 percent. A systematic review published in Molecular Biology Reports by Jiaju Xu, Chunxiao Ni, Ping Wang, Lidong Qin and colleagues now organizes the confusing landscape of biomarkers for this resistant population into a single framework, proposing a stratification model based on clinical actionability rather than on any single predictive test.

The review frames resistance to immune checkpoint inhibitors (ICIs) in MSS colorectal cancer as operating at three interconnected levels: intrinsic tumor defects, barriers within the tumor microenvironment, and what the authors describe as metastatic immune privilege. Each level, they argue, carries different implications for biomarker selection, which is why the authors recommend moving away from a one-marker-fits-all approach toward dynamic, host-integrated testing. At the top of their proposed hierarchy sit POLE and POLD1 mutations, which the NCCN Clinical Practice Guidelines in Oncology for Colon Cancer (Version 1.2025) have recommended; the review characterizes these as true genomic “hard” indicators of potential benefit.

Below that tier, the evidence becomes more conditional. The Immunoscore-IC predicted the benefit of ICI-containing combination regimens in the AtezoTRIBE trial, but the recently reported ANICCA-class II study questioned the value of anti-PD-1 monotherapy, suggesting the Immunoscore-IC may distinguish between combination and single-agent approaches rather than serving as a universal predictor. Three other candidate markers—defects in homologous recombination repair, ctDNA kinetics, and the CMS1 consensus molecular subtype—are described as promising but still requiring prospective validation before they can guide treatment decisions. Meanwhile, several widely discussed markers fared poorly in the review: tumor mutational burden showed no consistent value as a single biomarker, and microsatellite instability-like transcriptomic signatures and PD-L1 combined positive scores have not been proven useful in this setting.

Looking forward, the authors identify several strategies for improving patient selection. These include multiomics algorithms that integrate immune profiling with stromal determinants, liver-directed sensitizing approaches aimed at overcoming the immunologically privileged environment of metastatic disease, and serial ctDNA monitoring to track acquired resistance as it emerges during treatment. The review’s central message is that the field should abandon the static “cold tumor” paradigm for MSS colorectal cancer and instead pursue dynamic testing that accounts for the tumor, its microenvironment and the host together. As a systematic review, the work synthesizes existing trial and study data rather than presenting new clinical findings, and its proposed stratification model will need to be tested prospectively before it can change practice. Still, for a patient population whose options have remained stubbornly limited, the review offers a structured map of which biomarkers are ready for the clinic, which are awaiting validation, and which should be set aside.

Subject of Research: Biomarkers and future directions for immunotherapy in microsatellite-stable colorectal cancer

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

Article References: Xu, J., Ni, C., Wang, P., & Qin, L. (2026). Biomarkers and future directions for immunotherapy in microsatellite-stable colorectal cancer: a systematic review. Molecular Biology Reports, 53(1), Article 1801. https://doi.org/10.1007/s11033-026-13054-5

Image Credits: AI Generated

DOI: 10.1007/s11033-026-13054-5

Keywords: microsatellite-stable colorectal cancer, immune checkpoint inhibitors, biomarkers, POLE mutations, Immunoscore-IC, ctDNA, tumor mutational burden, CMS1, homologous recombination repair, systematic review, immunotherapy resistance, future