The tumor microbiome and cancer immunotherapy: A systematic review of a new frontier beyond the gut.

[BACKGROUND] While the gut microbiome is known to modulate systemic immunity and response to immune checkpoint inhibitors, the role of tumor-resident microbiota remains underexplored. Recent evidence suggests that these local microbial communities may influence intratumoral immunity and therapeutic outcomes.

[METHODS] A systematic review compliant with PRISMA guidelines was conducted to evaluate the impact of tumor-associated bacteria on anti-tumor immune responses. Four databases (PubMed, Scopus, Web of Science and EMBASE) were searched for studies published between January 2010 and April 2025. Eligible studies characterized non-intestinal microbiota within tumor tissue and assessed immune endpoints such as T cell infiltration, cytokine profiles, PD-L1 expression, or immune checkpoint inhibitors responsiveness. Due to endpoint heterogeneity, no meta-analysis was performed. Seventeen studies met inclusion criteria.

[RESULTS] In tumors including melanoma, pancreatic, esophageal, gastric, breast, lung, and colorectal cancers, intratumoral bacteria modulated immune responses and immune checkpoint inhibitors efficacy. Three recurring mechanisms emerged: immune activation via antigen presentation and Th1 polarization; immune suppression through regulatory T cell recruitment and stromal remodeling; and checkpoint modulation and T cell exhaustion via microbial signaling. These effects were spatially structured and tumor-context dependent.

[CONCLUSION] Tumor-local microbiota represents a distinct and actionable component of the tumor-immune microenvironment. Incorporating microbial profiling into immuno-oncology strategies may enhance biomarker discovery, patient stratification, and development of microbiome-based therapies. Further research is warranted to map spatial microbial heterogeneity, validate functional mechanisms, and translate findings into clinical applications in precision immunotherapy.