The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function

Highlights•METRNL is more highly expressed in CD8+ TIL than patient-matched PBMCs•METRNL exposure causes CD8+ T cell hypofunction due to bioenergetic insufficiency•METRNL decouples the electron transport chain in T cell mitochondria via E2F-PPARδ•METRNL ablation or knockdown delays tumor growth in tumor modelsSummaryTumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.Graphical abstract