Microbial Metabolites in Tumor Metabolic Reprogramming and Immunotherapy: New Insights

Yi Wang¹Dan Huang¹Rongrong Wang¹Jiaojiao Yin²Jianying Pei^2*Chong Zhang^2*

• ¹School of Public Health, Gansu University of Chinese Medicine, Lanzhou, China
• ²Department of Clinical Laboratory Centre, Gansu Provincial Maternity and Child Care Hospital, Lanzhou, China

Gut microbiota and intratumoral microbiota have been recognised as critical modulators of tumour development, with their metabolites exerting diverse effects on cancer progression. However, a comprehensive overview of the mechanisms through which microbial metabolites influence tumour metabolism and immunity is still lacking. This review summarises how microbial metabolites regulate glucose, lipid, and amino acid metabolism in cancer cells, impacting tumour growth, metastasis, and therapeutic responses. We highlight three major mechanistic layers: (1) direct regulation of metabolic enzymes, such as short-chain fatty acid(SCFAs)mediated inhibition of glycolytic enzymes; (2) modulation via signalling pathways, including the mTOR and HIF-1α axes; and (3) immunometabolic effects, particularly through the regulation of T cell effector functions and macrophage polarisation. Current challenges include inter-tissue variability in metabolite concentrations, methodological limitations for intratumoral metabolite detection, and the lack of standardised clinical cohorts. Finally, we propose future research directions integrating spatial metabolomics, stable isotope–based flux analysis, and single-cell profiling to accelerate translational research and facilitate metabolite-centred therapeutic strategies.