Work

NLRP3 signalling in NSCLC: distinguishing expression, inflammasome activation and context-dependent function

Year: 2026

Type: review

Abstract: Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related mortality despite advances in targeted therapy and immune checkpoint blockade. NLRP3-associated inflammation has attracted increasing interest in NSCLC, yet interpretation of the available evidence remains challenging because molecular expression, inflammasome activation, cytokine processing, pyroptotic execution and pathway dependence are frequently considered together. Here, we present a structured narrative review and an evidence framework that separates the biological event directly measured from the level of NLRP3-specific mechanistic support, while independently considering cellular source, disease relevance and treatment context. Current evidence indicates that NLRP3-specific mechanistic dependence in NSCLC has been demonstrated only in selected experimental settings, particularly treatment-conditioned macrophage models. Treatment-naïve human evidence reveals compartment-specific inflammasome-associated responses in alveolar macrophages and peripheral leukocytes but does not establish NLRP3 dependence. Tumour-cell studies support treatment-induced inflammasome- and pyroptosis-associated phenotypes, although causal attribution to NLRP3 is often incomplete. Single-cell and spatial studies mainly identify NLRP3-related transcriptional states or candidate microenvironmental niches and cannot, by themselves, demonstrate functional inflammasome activation or NLRP3-dependent interactions. Clinical trials targeting IL-1β provide evidence for downstream inflammatory modulation but do not directly evaluate NLRP3 inhibition. Overall, current evidence supports context-dependent NLRP3-associated biology in NSCLC rather than a uniform biomarker or therapeutic target. Future studies integrating cell-resolved localisation, activation-specific measurements, pathway perturbation and longitudinal validation are required to determine whether clinically relevant NLRP3-dependent states can be reproducibly identified.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1983973