Intratumoral microbial metabolites shape the tumor microenvironment and impact immunotherapy

The tumor microenvironment (TME) represents a highly complex system that encompasses cellular components (such as cancer cells, stromal cells, and immune cells) and non-cellular components (such as blood vessels and signaling molecules). These diverse components engage in complex interactions with tumor cells and undergo dynamic changes during tumor progression. Specifically, intratumoral microbial metabolites play an important role on the TME. The metabolic products of these microorganisms encompass a range of bioactive molecules, including lactate, amino acids, short-chain fatty acids (SCFAs), bile acids, trimethylamine N-oxide, and inosine. These metabolites, when released into the TME, can influence immune cell function through the modulation of cytokine secretion.

Considering the significant role of intratumoral microbial metabolites in the tumor microenvironment, these bioactive compounds may substantially impact cancer immunotherapy outcomes. Although extensive research has focused on gut microbiota-derived metabolites in tumor progression and cancer treatment, it is crucial to distinguish between metabolites from intratumoral microbes and those produced by gut microbiota. In this context, this review provides a systematic analysis of the role of intratumoral microbes in the tumor microenvironment and cancer immunotherapy, specifically examining how intratumoral microbes modulate the tumor microenvironment through: 1) glucose metabolites, 2) amino acids and their metabolites, 3) lipid metabolites, and 4) other metabolites, ultimately affecting the clinical benefits of immunotherapy. Furthermore, this review presents a systematic and comprehensive analysis of the mechanisms by which intratumoral microbial metabolites function in the tumor microenvironment and investigates the potential connections between these metabolites and immunotherapy efficacy, with the objective of establishing theoretical foundations and research directions for novel cancer treatment strategies, while fostering interdisciplinary integration among microbiology, oncology, and immunology.