ArticleJournal for immunotherapy of cancer2025
Macrophage NLRP3 activation and IL-1β release drive osimertinib-induced antitumor immunity.
Article in Journal for immunotherapy of cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- The molecular mechanisms of pyroptosis and its implications in tumor immunotherapy.Molecular cancer · 2026Review
- Mechanisms and therapeutic prospects of DNA methylation-mucosal innate immunity crosstalk in inflammatory bowel disease.Frontiers in immunology · 2026Review
- NLRP3 inflammasomes at the ARDS-cancer interface: mechanisms and translational hypotheses.Frontiers in immunology · 2026Review
- Tumor-associated macrophages in cancer: from mechanisms to application.Molecular biomedicine · 2025Review
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Authors and funding
10 authors.
Funding
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Abstract
backgroundDespite 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.
methodsUsing 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.
resultsOsimertinib triggered NLRP3 inflammasome activation in macrophages via lysosomal dysfunction-induced calcium overload, leading to mitochondrial damage and ROS production, which acted as damage-associated molecular patterns to activate NLRP3. This process promoted IL-1β release, pyroptosis, and CD8
conclusionsOsimertinib exerts off-target immunomodulatory effects by activating the tumor-extrinsic NLRP3 inflammasome, linking mitochondrial-lysosomal crosstalk to antitumor immunity. NLRP3 and IL-1β in TAMs emerge as predictive biomarkers for EGFR-TKI efficacy, while rIL-1β combination therapy represents a novel strategy to enhance clinical outcomes.
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