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<p>Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4 pathways have revolutionized cancer therapy, yet their efficacy is frequently limited by primary or secondary resistance. Emerging evidence underscores the gut microbiota as a decisive regulator of ICI therapeutic outcomes. This review systematically delineates the multi-dimensional mechanisms through which the microbiota modulates anti-tumor immunity, specifically focusing on the molecular remodeling of immune signaling by microbial metabolites such as short-chain fatty acids (SCFAs) and bile acids, cross-reactive immunity driven by antigenic molecular mimicry, and the spatial restructuring of the tumor microenvironment mediated by the gut-tumor axis. Clinically, fecal microbiota transplantation (FMT) has demonstrated the potential to reverse ICI resistance, while the development of live biotherapeutic products (LBPs) and precise prebiotic combinations offers a standardized path for niche-specific intervention. Despite these advances, critical challenges persist, including the biological mismatch in cross-species animal models, the context-dependency arising from individualized microbial signatures, and the cognitive gap in the temporal dynamics of microbe-drug interactions. Deciphering the non-linear correlation between microbial succession and host immune response will be essential for integrating microbiota-driven strategies into personalized oncology frameworks.</p>

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Harnessing the gut microbiota to enhance immune checkpoint inhibitor efficacy: from mechanistic insights to clinical translation

  • 期刊论文

  • 发表日期：

    2026年5月22日

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  • Qinsheng Bi,
  • Liangyi Zhang,
  • Hejia Wan,
  • Jiaxin Zhang

摘要

Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4 pathways have revolutionized cancer therapy, yet their efficacy is frequently limited by primary or secondary resistance. Emerging evidence underscores the gut microbiota as a decisive regulator of ICI therapeutic outcomes. This review systematically delineates the multi-dimensional mechanisms through which the microbiota modulates anti-tumor immunity, specifically focusing on the molecular remodeling of immune signaling by microbial metabolites such as short-chain fatty acids (SCFAs) and bile acids, cross-reactive immunity driven by antigenic molecular mimicry, and the spatial restructuring of the tumor microenvironment mediated by the gut-tumor axis. Clinically, fecal microbiota transplantation (FMT) has demonstrated the potential to reverse ICI resistance, while the development of live biotherapeutic products (LBPs) and precise prebiotic combinations offers a standardized path for niche-specific intervention. Despite these advances, critical challenges persist, including the biological mismatch in cross-species animal models, the context-dependency arising from individualized microbial signatures, and the cognitive gap in the temporal dynamics of microbe-drug interactions. Deciphering the non-linear correlation between microbial succession and host immune response will be essential for integrating microbiota-driven strategies into personalized oncology frameworks.