Compartment-specific PPARδ activity controls the outcome of cancer–immune cell competition and immunotherapy efficacy

Nature Immunology

Most patients with solid tumors fail to sustain antitumor immunity, in part because immune cells cannot outcompete cancer cells inside the immunosuppressive tumor microenvironment. Here, we show the lipid-sensing transcription factor PPARδ is a compartment-specific determinant of cancer–immune fitness balance and immunotherapy efficacy. Activating PPARδ in cancer cells promotes their growth and impairs antitumor immunity, whereas activating it in immune cells drives tumor suppression and overrides tumor-promoting effects of cancer-intrinsic activation. Mechanistically, PPARδ enhances CD8+ T cell fitness against cancer through effector-associated chromatin remodeling and Cpt1a-mediated fatty acid oxidation. These findings identify compartment-specific PPARδ activity as a targetable driver of immune cell fitness that can be harnessed to improve outcomes in immunotherapy-resistant tumors.

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Compartment-specific PPARδ activity controls the outcome of cancer–immune cell competition and immunotherapy efficacy