%0 Journal Article
%T The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function.
%A Jackson CM
%A Pant A
%A Dinalankara W
%A Choi J
%A Jain A
%A Nitta R
%A Yazigi E
%A Saleh L
%A Zhao L
%A Nirschl TR
%A Kochel CM
%A Hwa-Lin Bergsneider B
%A Routkevitch D
%A Patel K
%A Cho KB
%A Tzeng S
%A Neshat SY
%A Kim YH
%A Smith BJ
%A Ramello MC
%A Sotillo E
%A Wang X
%A Green JJ
%A Bettegowda C
%A Li G
%A Brem H
%A Mackall CL
%A Pardoll DM
%A Drake CG
%A Marchionni L
%A Lim M
%J Immunity
%V 57
%N 8
%D 2024 Aug 13
%M 39111315
%F 43.474
%R 10.1016/j.immuni.2024.07.003
%X Tumor-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.