Applications of traditional Chinese medicine in cancer immunotherapy via gut microbiota modulation: Current status, mechanisms, challenges and perspectives

Cancer immunotherapy faces significant limitations due to therapeutic resistance. Emerging evidences have identified the gut microbiota (GM) as a crucial regulator of antitumor immunity through its effects on the tumor immune microenvironment (TIME). Guided by the principle of "fu zheng qu xie" (fortifying healthy qi to reinforce immune homeostasis and eliminating pathogenic factors to promote immune clearance), traditional Chinese medicine (TCM) exerts multi-target systemic regulation. Specifically, TCM modulates gut microecology, which in turn regulates the production of microbial metabolites (e.g., short-chain fatty acids, bile acids), ultimately reprogramming TIME by enhancing immune cell infiltration into the tumor parenchyma, optimizing T-cell cytotoxicity and differentiation, improving antigen presentation, and alleviating immunosuppression. This review systematically summarizes the causal chain of "TCMGMmetabolitesimmune cellsTIME" across different immune phenotypes, emphasizing how bioactive TCM components and classical formulas reshape microbial communities, enrich beneficial bacteria, and regulate metabolic pathways to potentiate cancer immunotherapy. Despite promising preclinical data, challenges persist due to mechanistic complexity, the lack of standardization, and limited clinical translation. Potential solutions include multi-omics integration, intelligent screening of herbal compounds, and targeted delivery systems. With advancing pharmacological insights, TCM-derived microbiome modulators (TMMs), defined as phytochemicals and formulations that systematically modulate gut microecology, may overcome immunotherapy resistance, representing a novel strategy for enhancing cancer immunotherapy.