Decoding and exploiting intratumoral microbiota: from microenvironment modulation to clinical intervention.

Intratumoral microbiota are increasingly recognized as essential components of the tumor microenvironment (TME) across various cancer types. This review emphasizes the regulatory roles of these microbial communities in modulating the TME and discusses their potential as targets for clinical intervention. Intratumoral microbiota contribute to an immunosuppressive TME through several mechanisms that promote tumor progression and affect therapeutic responses. They directly stimulate oncogenic pathways such as PI3K-AKT, induce chronic inflammation via NF-κB activation mediated by pattern recognition receptors, and impair CD8 + T cell function by recruiting regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) or by secreting metabolites like short-chain fatty acids. These actions create a microenvironment that supports tumor growth. In the context of immunotherapy, certain microbial species can undermine the effectiveness of immune checkpoint inhibitors by upregulating PD-L1 expression or expanding immunosuppressive cell populations. Building on the understanding of microbe-TME interactions, novel intervention strategies are being developed. Techniques such as engineered bacteria, bacteriophage therapy, and bacterial extracellular vesicles (BEVs) have shown promise in remodeling the TME, overcoming therapy resistance, and enhancing the effectiveness of immunotherapy. Despite these advancements, significant challenges remain. These include deciphering the spatiotemporal dynamics of intratumoral microbiota, elucidating their mechanistic interactions with host cells, and ensuring safe and effective clinical translation. Future research that integrates spatial multi-omics, synthetic biology, and nanotechnology may lead to precision therapeutic paradigms focused on microbiota-TME modulation, offering innovative solutions to address tumor resistance.