PPARa Inhibition Overcomes Tumor Derived Exosomal Lipids-Induced Dendritic Cell Dysfunction

Dendritic cells orchestrate the initiation, programming, and regulation of anti-tumor immune responses. Emerging evidence indicates that the tumor microenvironment (TME) induces immune dysfunctional tumor-infiltrating DC (TIDC), characterized by 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 DC to promote immune evasion. Mechanistically, peroxisome proliferator-activated receptor (PPAR)a 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 towards mitochondrial oxidative phosphorylation which drives DC immune dysfunction. Genetic depletion or pharmacologic inhibition of PPARa 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 PPARa lies at the center of metabolic-immune regulation of DCs, suggesting a potential immunotherapeutic target.