The immunomodulatory effects of intratumoral microbiota on tumor initiation, progression, and metastasis: From understanding to therapy.

The human body harbors a diverse array of microbial communities, including bacteria, viruses, and fungi. Recent advancements in high-throughput sequencing technology have revealed the presence of bacterial DNA within tumor cells, challenging the long-held belief that tumor tissues are sterile. The tumor immune microenvironment (TIME) is a complex and dynamic system comprising tumor cells, immune cells, and cytokines. These components interact intricately, playing crucial roles in tumor initiation, progression, and metastasis. This review systematically examines the alterations in the TIME across different stages of tumor progression, providing a comprehensive immunological perspective to elucidate the mechanisms underlying tumorigenesis and development. Additionally, we explore the origins and characteristics of intratumoral microorganisms, which are significant components of tumors, as well as the immunoregulatory mechanisms that drive their impact on tumor progression. Finally, we highlight the stage-heterogeneity and tissue-specificity of intratumoral microbiota and microbial metabolites in modulating TIME, and discuss recent breakthroughs and emerging therapeutic strategies targeting this crosstalk, including immunotherapies, drug delivery systems and pharmaceutical interventions, aiming to enhance anti-tumor immunity and improve clinical outcomes.