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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. This was consistent with clinical observations that more tumor‐infiltrating CD8 +  T cells and elevated peripheral IFN‐α before receiving nivolumab treatment were associated with a longer PFS in NSCLC patients. Our study highlights the roles of tumor‐intrinsic NLRP4 in remodeling the immune contextures in the tumor microenvironment, making regional type I IFN beneficial for ICI treatment.

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