Abstract / Summary
The discovery of intratumoral microbiota has challenged the traditional view of tumors as sterile environments and revealed a previously unrecognized layer of complexity within the tumor microenvironment (TME). Accumulating evidence indicates that microorganisms residing in tumors are not merely passive inhabitants but dynamic ecological regulators that influence tumor evolution, immune remodeling, and therapeutic responses. However, the biological functions of intratumoral microbiota cannot be determined solely by microbial identity, but are shaped by microbial traits, spatial localization, tumor characteristics, and therapeutic pressure. In this review, we summarize recent advances in the origins, heterogeneity and dynamic evolution of intratumoral microbiota, while discussing emerging technologies and methodological challenges associated with characterizing low-biomass microbial ecosystems. We further highlight how intratumoral microorganisms influence tumor immunity and emerging microbiota-targeted strategies to reprogram the TME, with particular emphasis on microbiota-driven remodeling of adaptive and innate immune ecosystems. Furthermore, we discuss the emerging role of intratumoral microbiota on the efficacy of immune checkpoint inhibitors (ICIs). Importantly, microbial effects on immunotherapy are not only context-dependent but may appear paradoxical, with the same microorganism exhibiting opposing biological effects under different ecological and therapeutic conditions. By integrating microbial ecology with tumor immunology and therapeutic intervention, we propose a tripartite framework—microbiota–immunity–therapy—to re-evaluate the architecture of the tumor ecosystem and to position intratumoral microbiota as a dynamic regulator of immunotherapy response and promising therapeutic targets.