Targeting NLRP3 inflammasome: a novel strategy for improving immune checkpoint inhibitor-associated pneumonitis

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but are frequently accompanied by immune-related adverse events (irAEs) affecting multi-organ. Checkpoint inhibitor-associated pneumonitis (CIP) is a serious irAE whose mechanistic underpinnings remain poorly understood, limiting the clinical application of ICIs. The objective of this study was to investigate the role of the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome in the pathogenesis of CIP and to explore potential targeted therapies.

A CIP mouse model was established via regulatory T cell (Treg) depletion and anti-programmed cell death protein 1 (PD-1) antibody treatment. Lung tissue gene expression was analyzed using RNA-sequencing, quantitative polymerase chain reaction (qPCR), and Western blot. Therapeutic interventions with NLRP3 inflammasome inhibitors (MCC950 and dapansutrile) and a macrophage-depleting agent (clodronate liposomes) were evaluated by micro-computed tomography (CT), histopathology, and serum inflammatory cytokine assays. Validation was performed via single-cell transcriptomic analysis of bronchoalveolar lavage fluid from 13 non-small cell lung cancer patients with or without ICI-induced CIP.

The findings revealed: (I) significant upregulation of NLRP3 inflammasome pathway-related genes and downstream factors (IL-1β, IL-18) in CIP mouse lungs, alongside increased macrophage infiltration; (II) pneumonitis injury was markedly alleviated and serum inflammatory cytokine levels were reduced by both NLRP3 inflammasome inhibition and macrophage depletion; (III) dapansutrile downregulated NLRP3 expression via inhibition of the NF-κB pathway; (IV) enriched macrophage subpopulations (Mac-IL1B) expressing high levels of NLRP3 were identified in CIP patients.

This study provides the first evidence that NLRP3 inflammasome activation constitutes a key upstream mechanism in CIP pathogenesis, offering novel therapeutic strategies for targeted intervention.