{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:04:27Z","timestamp":1789747467472,"version":"4.0.1"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>To evaluate the potential of TCM to regulate immune-resistance mechanisms in MSS-CRC and to propose a barrier-oriented framework for rational TCM\u2013ICI combination strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\u2013B-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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1874066","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T05:39:54Z","timestamp":1782711594000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["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"],"prefix":"10.3389","volume":"17","author":[{"given":"Dawei","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, The Third Affiliated Hospital of Shandong First Medical University (Affiliated Hospital of Shandong Academy of Medical Sciences)","place":["Jinan, Shandong, China"]},{"name":"Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yawei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The Third Affiliated Hospital of Shandong First Medical University (Affiliated Hospital of Shandong Academy of Medical Sciences)","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, The Third Affiliated Hospital of Shandong First Medical University (Affiliated Hospital of Shandong Academy of Medical Sciences)","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2017699","article-title":"Pembrolizumab in microsatellite-instability-high advanced colorectal cancer","volume":"383","author":"Andr\u00e9","year":"2020","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-023-03520-5","article-title":"PD-1 and PD-L1 inhibitors in cold colorectal cancer: challenges and strategies","volume":"72","author":"Lin","year":"2023","journal-title":"Cancer Immunol Immunother"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13174345","article-title":"Immune-checkpoint inhibitors for metastatic colorectal cancer: a systematic review of clinical outcomes","volume":"13","author":"Shek","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/postmj\/qgad136","article-title":"Immunotherapy of microsatellite stable colorectal cancer: resistance mechanisms and treatment strategies","volume":"100","author":"Han","year":"2024","journal-title":"Postgrad Med J"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13785","article-title":"A new strategy for immunotherapy of microsatellite-stable (MSS)-type advanced colorectal cancer: multi-pathway combination therapy with PD-1\/PD-L1 inhibitors","volume":"173","author":"Cai","year":"2024","journal-title":"Immunology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1186\/s12876-022-02511-7","article-title":"Efficacy and safety of anti-PD-1\/PD-L1 therapy in the treatment of advanced colorectal cancer: a meta-analysis","volume":"22","author":"Li","year":"2022","journal-title":"BMC Gastroenterol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/molecules30132686","article-title":"Focus on PD-1\/PD-L1-targeting antibodies in colorectal cancer: are there options beyond dostarlimab, nivolumab, and pembrolizumab? 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