Intratumoral microbiota in cancer: molecular mechanism and therapeutic strategies

Recent spatially resolved, multi-omic, and functional studies have advanced understanding of the intratumoral microbiota (ITM), shifting attention from microbial detection in tumors to how microbial localization and host-cell interactions influence cancer phenotypes and therapeutic outcomes. In this review, we first trace the historical development of the field and synthesize current evidence on routes of microbial colonization, pan-cancer heterogeneity, and the spatial organization of ITM. We then discuss how ITM directly affects genomic stability, signaling pathways, metabolism, and cellular plasticity of cancer cells, while indirectly shaping tumor evolution through its effects on immune and stromal components within the tumor microenvironment (TME). We further assess the role of ITM in anticancer therapy, explicitly distinguishing mechanisms supported by direct evidence in tumors from those inferred primarily from gut microbiota-driven systemic effects. In addition, we summarize emerging strategies to target or exploit ITM, including antibiotics, phage strategy, engineered strategy and related microbiota-modulating interventions. Finally, we highlight the major challenges that continue to constrain the field, particularly low microbial biomass, contamination, limited spatial resolution, and insufficient in vivo functional validation. Together, these considerations position ITM as a context-dependent component of tumor ecosystems with potential relevance to tumor progression, therapeutic stratification, and biomarker development, while defining priorities for more rigorous and clinically actionable research.