Enhancing CD8⁺ T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy

How tumor-infiltrating T lymphocytes (TILs) adapt to the metabolic constrains within the tumor microenvironment (TME) and to what degree this affects their ability to combat tumor progression remain poorly understood. Using mouse melanoma models, we report that CD8⁺ TILs enhance peroxisome proliferator-activated receptor (PPAR)-α signaling and catabolism of fatty acids (FAs) when simultaneously subjected to hypoglycemia and hypoxia. This metabolic switch partially preserves CD8⁺ TILs' effector functions, although co-inhibitor expression increases during tumor progression regardless of CD8⁺ TILs' antigen specificity. Further promoting FA catabolism improves the CD8⁺ TILs' ability to slow tumor progression. PD-1 blockade delays tumor growth without changing TIL metabolism or functions. It synergizes with metabolic reprogramming of T cells to achieve superior antitumor efficacy and even complete cures. Zhang et al. show that CD8⁺ T cells enhance PPAR-α signaling and fatty acid catabolism under the hypoglycemic and hypoxic condition to partially preserve effector functions. Metabolic reprogramming of T cells using a PPAR-α agonist improves tumor growth control, which is enhanced in combination with PD-1 blockade.