PPARα Inhibition Overcomes Tumor-Derived Exosomal Lipid-Induced Dendritic Cell Dysfunction

Dendritic cells (DCs) orchestrate the initiation, programming, and regulation of anti-tumor immune responses. Emerging evidence indicates that the tumor microenvironment (TME) induces immune dysfunctional tumor-infiltrating DCs (TIDCs), characterized with both increased intracellular lipid content and mitochondrial respiration. The underlying mechanism, however, remains largely unclear. Here, we report that fatty acid-carrying tumor-derived exosomes (TDEs) induce immune dysfunctional DCs to promote immune evasion. Mechanistically, peroxisome proliferator activated receptor (PPAR) α responds to the fatty acids delivered by TDEs, resulting in excess lipid droplet biogenesis and enhanced fatty acid oxidation (FAO), culminating in a metabolic shift toward mitochondrial oxidative phosphorylation, which drives DC immune dysfunction. Genetic depletion or pharmacologic inhibition of PPARα effectively attenuates TDE-induced DC-based immune dysfunction and enhances the efficacy of immunotherapy. This work uncovers a role for TDE-mediated immune modulation in DCs and reveals that PPARα lies at the center of metabolic-immune regulation of DCs, suggesting a potential immunotherapeutic target. [Display omitted] •Tumor-derived exosomes (TDEs) drive DC dysfunction•TDE-derived fatty acids activate PPARα to induce DC fatty acid oxidation•PPARα blockade modulates lipid metabolism and function in DCs•PPARα inhibition enhances the anti-tumor efficacy of immunotherapies Yin et al. reveal that tumor-derived exosomes (TDEs), as fatty acid carriers, induce a metabolic shift toward oxidative phosphorylation, driving DC immune dysfunction. Transcriptomic analysis identifies PPARα as the fatty acid sensor mediating the immunosuppressive effects of TDEs on DCs. PPARα blockade effectively restores DC function and enhances the efficacy of immunotherapy.