Traditional Chinese medicine as a potential barrier-oriented sensitization strategy for immune checkpoint blockade in microsatellite-stable colorectal cancer: from resistance mechanisms to translational validation.

Background: Microsatellite-stable colorectal cancer (MSS-CRC) is refractory to immune checkpoint inhibitors (ICIs), mainly because of low tumor immunogenicity, impaired antigen presentation, immune exclusion, and myeloid- or Treg-dominated immunosuppression. Traditional Chinese medicine (TCM), characterized by multi-component and multi-target regulation, may provide complementary approaches for modulating these resistance barriers. This review summarizes the rationale, evidence, and translational requirements for integrating TCM with ICI-based therapy in MSS-CRC. Purpose: To evaluate the potential of TCM to regulate immune-resistance mechanisms in MSS-CRC and to propose a barrier-oriented framework for rational TCM-ICI combination strategies. Methods: A structured narrative review was conducted in PubMed, Web of Science, Embase, Scopus, CNKI, and Wanfang for studies published from January 2019 to March 2026. Searches covered MSS/pMMR CRC, immune checkpoint blockade, TCM interventions, tumor microenvironment, microbiota, immunometabolism, syndrome patterns, active constituents, and herbal quality control. Eligible studies addressed MSS/pMMR CRC immunotherapy, TCM or phytomedicine-based interventions, or immune-resistance mechanisms. Direct MSS/pMMR CRC studies involving ICI combinations were prioritized, while broader CRC, cross-cancer, pharmacological, and computational studies were used as supportive evidence. Results: Selected TCM interventions may improve ICI responsiveness in MSS-CRC when matched to specific resistance barriers. Representative interventions include Zhenqi Fuzheng Granules, Shenqi Yichang Formula, Gegen Qinlian Decoction, modified Shenling Baizhu San, Changweiqing, and electroacupuncture-related evidence. These interventions have been linked to immunometabolic remodeling, dendritic-cell mitophagy and antigen presentation, microbiota-driven TME remodeling, Tfh-B-cell interactions, and STING-dependent immune activation. However, direct formula-specific clinical evidence for ICI sensitization in molecularly defined MSS-CRC remains limited. Clinical-translational evidence includes an early phase II study of electroacupuncture combined with fruquintinib and sintilimab in refractory MSS-mCRC, whereas most herbal-formula evidence remains preclinical or indirect. We therefore propose matching TCM interventions and active ingredients to dominant immune-resistance phenotypes and integrating syndrome-informed host-state stratification. These hypotheses require validation using causal assays, organoid-immune co-culture, single-cell/spatial omics, pharmacological standardization, and biomarker-enriched clinical trials. Conclusion: TCM may serve as a complementary, mechanism-informed candidate sensitization strategy for MSS-CRC immunotherapy, but it is not an established standard combination approach. Future translation requires formula-specific and component-level validation, reproducible immune and microbiota-metabolic biomarkers, TCM syndrome assessment, herbal quality control, safety monitoring, and clinically meaningful outcomes.