Influence of pirfenidone on checkpoint inhibitor pneumonitis and antitumor efficacy in NSCLC: A multicenter study and mechanistic exploration.

2609 Background: Checkpoint inhibitor pneumonitis (CIP) is a major fatal immune-related adverse events (irAEs) in immune checkpoint inhibitor (ICI) therapy, accounting for ~35% of fatal irAE-related deaths. Patients with pre-existing interstitial lung disease (ILD) face markedly higher CIP risk and are routinely excluded from ICI treatment, depriving them of antitumor benefits. Current first-line glucocorticoid therapy for CIP are limited by inadequate efficacy in fibrotic-stage or steroid-resistant CIP and impaired ICI activity. As a drug-induced interstitial pneumonitis, CIP shares pathological similarities with ILD. Pirfenidone, an approved ILD drug, showed potential efficacy in CIP case reports, but its systematic clinical value and mechanisms remain unvalidated. This study aimed to elucidate pirfenidone's role in full-cycle CIP management and its synergistic antitumor effect with ICIs. Methods: A multicenter retrospective study enrolled advanced non-small cell lung cancer (NSCLC) patients receiving first-line ICI-based therapy from three hospitals between 2018 and 2024, stratifying into pirfenidone+ICI+chemotherapy (Pirf+ICI+chemo) and ICI+chemotherapy (ICI+chemo) groups. Primary endpoint was CIP incidence, secondary endpoints objective response rate (ORR) and progression-free survival (PFS). For mechanistic studies, bleomycin and ICI were administered to spontaneous NSCLC mice to mimic clinical ICI treatment in ILD-high-risk patients, generating a CIP mouse model. Lung scRNA-seq defined pirfenidone's role in CIP management and synergistic antitumor activity. Results: Of 141 enrolled patients, Pirf+ICI+chemo had significantly lower CIP incidence vs. ICI+chemo (34.01% vs. 59.57%, p =0.0070), with synergistic antitumor effects manifested as higher ORR (78.72% vs. 60.64%, p =0.0376), and longer median PFS (9.97 vs. 5.47 m, p =0.0120). CIP shows a biphasic inflammation-fibrosis pathology. scRNA-seq of 62,335 lung cells identified ISG + aged neutrophils (ISG + Na) as the key pathogenic driver of CIP progression. ICI-induced excessive immune activation triggers lung damage, activating the IFN-I-IRF9/STAT1 axis to promote ISG + Na differentiation. These cells secrete IL-6, IL-8, TNF-α to amplify inflammation, and TGF-β to induce fibroblast proliferation and activation, all of which pirfenidone blocks, supporting its full-cycle CIP efficacy mechanistically. Animal experiments further confirmed pirfenidone's robust efficacy in CIP prevention, treatment and synergistic antitumor activity with ICI. Conclusions: Pirfenidone reduces CIP incidence and synergizes with ICI therapy to enhance antitumor efficacy. Mechanistically, it targets IFN-I-IRF9/STAT1-ISG + Na axis for dual clinical benefits. These findings confirm pirfenidone as a translatable strategy to balance CIP control and antitumor activity.