Fatty Allies: How Short-Chain Fatty Acids Turn the Tumor Microenvironment Against Cancer

Short-chain fatty acids (SCFAs), which are fatty acids with fewer than six carbon atoms, are primarily produced by gut microbiota through fermentation of dietary fibers. They interact with various receptors on target cells, including G-protein coupled receptors (GPCRs) and free fatty acid receptors (FFARs). These interactions induce significant epigenetic modifications, such as the inhibition of histone deacetylases (HDACs) and the regulation of several microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). SCFAs reprogram the tumor microenvironment (TME) by promoting the recruitment and effector function of cluster of differentiation (CD)8⁺ T cells and reducing regulatory T cell (Treg) activity, thereby converting the TME from an immunosuppressive to an immunoreactive state. They modulate the differentiation and activity of various immune cell subsets, including macrophages, dendritic cells (DCs), natural killer (NK) cells, neutrophils, T cells, B cells, and myeloid-derived suppressor cells (MDSCs). SCFAs also precipitate anti-growth effects in tumor cells by hampering glycolysis and enhancing fatty acid oxidation. The idea of integrating SCFAs with immunotherapy for cancer treatment has garnered considerable interest in recent years. However, more work is still needed to better understand the molecular underpinnings of the interaction between SCFAs and different cell subsets within the TME. Further investigation of issues relating to dosing, therapeutic efficacy, and safety of exogenously administered SCFAs in cancer patients, particularly immunocompromised patients, is also in order.