Macrophage NLRP3 activation and IL-1β release drive osimertinib-induced antitumor immunity

作者：Haiyang Yu, Xin Sun, Yan Li, Jing Pan, Xumei Liu, Hongbin He, Haibo Wu, Yubei Sun, Yueyin Pan, Xiao-Jun Qian · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2025-012182 · 被引用次数：7 · 研究领域：Inflammasome and immune disorders、Cancer Immunotherapy and Biomarkers、Lung Cancer Treatments and Mutations

BACKGROUND: Despite the clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC), patient outcomes vary even among those with identical EGFR mutations. This study investigates whether osimertinib, a third-generation EGFR-TKI, activates the nucleotide-binding oligomerization domain-like receptor protein-3 (NLRP3) inflammasome in macrophages to drive antitumor immunity and explores its mechanistic basis. METHODS: Using bone marrow-derived macrophages from wild-type and gene-deficient mice, human peripheral blood mononuclear cells, and a Lewis lung cancer murine model, we assessed osimertinib-induced NLRP3 inflammasome activation, interleukin (IL)-1β secretion, pyroptosis, and tumor microenvironment (TME) remodeling. Mechanistic studies evaluated lysosomal dysfunction, calcium overload, mitochondrial damage, and reactive oxygen species (ROS) production. Clinical correlations were analyzed in patients with NSCLC treated with EGFR-TKIs. RESULTS: T-cell activation while suppressing regulatory T cells in the TME. In murine models, osimertinib's antitumor effects were abrogated by NLRP3 inhibition (MCC950) and enhanced by recombinant IL-1β (rIL-1β) co-administration (p<0.01). Clinically, high NLRP3 and IL-1β expression in tumor-associated macrophages (TAMs) correlated with prolonged progression-free survival (p<0.01) and overall survival (p<0.01) in EGFR-TKI-treated patients with NSCLC. CONCLUSIONS: Osimertinib...