FFAR2 (GPR43) is a G protein-coupled receptor activated by short-chain fatty acids (SCFAs)—acetate, propionate, and butyrate—produced by gut microbiota fermentation of dietary fiber 1. Upon SCFA binding, FFAR2 couples to Gi/o and Gq proteins, triggering calcium mobilization, MAPK phosphorylation, and cAMP inhibition 1. The receptor exhibits constitutive activity independent of SCFA binding. FFAR2 regulates energy homeostasis by modulating GLP-1 and leptin secretion, controlling glucose metabolism and adipogenesis 1. Critically, FFAR2 maintains intestinal immune tolerance by promoting regulatory T cell (Treg) differentiation and colonic Treg homeostasis in an SCFA-dependent manner, protecting against colitis 2. The receptor also mediates immune responses by regulating chemokine and cytokine production, with implications for inflammatory bowel disease pathogenesis and treatment 3. In cancer, FFAR2 expressed on myeloid-derived suppressor cells drives immunosuppression through acetic acid signaling via Gαq/calcium/PPAR-γ/Arg1 axes, promoting L-arginine depletion and T cell dysfunction 4. FFAR2 inhibition enhances anti-tumor CD8+ T cell responses and overcomes checkpoint blockade resistance 4. Additionally, FFAR2 mediates butyrate-induced ferroptosis in tumor cells via mTOR signaling 5, suggesting dual therapeutic potential in cancer immunotherapy and treatment.