Meteorin-like protein in cancer immune evasion
The cytokine Meteorin-like inhibits anti-tumor CD8
Tumor-infiltrating lymphocyte (TIL) hypofunction plays a key role in the progression of advanced cancers and is a common target for immunotherapy. Emerging evidence suggests that metabolic deficiencies contribute to T cell dysfunction during tonic stimulation, but the signals triggering metabolic reprogramming in this context are still poorly understood. In this study, we identified Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells within the tumor microenvironment (TME), as a factor causing bioenergetic failure in CD8+ T cells. METRNL was released by CD8+ T cells after repeated stimulation and acted through both autocrine and paracrine signaling mechanisms. We found that METRNL enhanced E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, leading to mitochondrial depolarization and reduced oxidative phosphorylation. This triggered a compensatory shift in bioenergetics towards glycolysis. Deleting or downregulating Metrnl improved the metabolic health of CD8+ T cells and boosted tumor control in several tumor models, suggesting that targeting the METRNL-E2F-PPARδ pathway may be a promising strategy to enhance the bioenergetic fitness of CD8+ TILs.
