Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity

T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8+ tumor-infiltrating lymphocytes, terminally subset contributes directly tumor killing owing its cytotoxic effector function. However, this does not respond immune checkpoint blockades and is difficult be reinvigorated with restored proliferative capacity. Here, we show that a half-life-extended interleukin-10–Fc fusion protein potently enhanced expansion function lymphocytes by promoting oxidative phosphorylation, process was independent progenitor cells. Interleukin-10–Fc safe highly efficient metabolic intervention synergized adoptive transfer immunotherapy, leading eradication established solid tumors durable cures in majority treated mice. These findings reprogramming upregulating mitochondrial pyruvate carrier-dependent phosphorylation can revitalize cells enhance response Tang colleagues IL-10–Fc acts on PD1+TIM-3+CD8+ their proliferation cellular metabolism carrier–dependent manner. Treatment tumor-bearing mice therapy led cures.