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

Here, we identify the lipid-sensing transcription factor PPARδ as a compartment-specific determinant of cancer-immune fitness balance and immunotherapy efficacy. Activating PPARδ in cancer cells promotes their growth and impairs anti-tumor 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 and remodeling and Cpt1a-mediated fatty acid oxidation, which is partly necessary but not sufficient.Therapeutically, PPARδ-activated CD8+ T cells sensitize immunotherapy resistant microsatellite stable (MSS) metastatic colorectal cancer to checkpoint blockade in mice, and pharmacologic or genetic PPARδ activation enhances human CAR-T cell function.

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.