Accumulation of branched-chain amino acids reprograms glucose metabolism in CD8 T cells with enhanced effector function and anti-tumor response.

Branched-chain amino acids (BCAAs) provide nutrient signals for cell survival and growth. How BCAAs affect CD8 T cell functions remains unexplored. Herein, we report that accumulation of BCAAs in CD8 T cells due to the impairment of BCAA degradation in 2C-type serine/threonine protein phosphatase (PP2Cm)-deficient mice leads to hyper-activity of CD8 T cells and enhanced anti-tumor immunity.

NLRP4 negatively regulates type I interferon response and influences the outcome in anti-programmed cell death protein (PD)-1/PD-ligand 1 therapy.

The challenge to improve the clinical efficacy and enlarge the population that benefits from immune checkpoint inhibitors (ICIs) for non-small-cell lung cancer (NSCLC) is significant. Based on whole-exosome sequencing analysis of biopsies from NSCLC patients before anti-programmed cell death protein-2 (PD-1) treatment, we identified NLRP4 mutations in the responders with a longer progression-free survival (PFS). Knockdown of NLRP4 in mouse Lewis lung cancer cell line enhanced interferon (IFN)-α/β production through the cGAS-STING-IRF3/IRF7 axis and promoted the accumulation of intratumoral CD8 T cells, leading to tumor growth retardation in vivo and a synergistic effect with anti-PD-ligand 1 therapy.