Tumour hepcidin levels as a biomarker for predicting response to immune checkpoint inhibition in advanced non‐small cell lung cancer

Abstract Background Hepcidin, a key regulator of iron homeostasis, is often overexpressed in non‐small cell lung cancer (NSCLC). While hepcidin renders cells susceptible to ferroptosis, which is linked to the activity of programmed cell death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) inhibitors, its clinical impact on immunotherapy efficacy remains unclear. Methods We retrospectively analyzed patients with advanced NSCLC who received anti‐PD‐1/PD‐L1 monotherapy. Patients were stratified into two groups based on immunohistochemical analysis: high hepcidin expression (tumour proportion score [TPS] = 50%, n = 6) and none‐to‐moderate expression (TPS 0–49%, n = 39). Treatment duration, progression‐free survival (PFS), and overall survival (OS) were compared. In vitro mechanisms were also explored using hepcidin and interferon‐gamma (IFNg) co‐culture models. Results The high‐hepcidin group exhibited a longer median treatment duration (42 vs. 5 days; p = 0.051). This group also showed improved PFS (2222 vs. 126 days; hazard ratio [HR], 0.35 [95% CI, 0.16–0.79]; p = 0.0643) and OS (not reached vs. 459 days; HR, 0.46 [95% CI, 0.18–1.16]; p = 0.0994), although these differences did not reach statistical significance. In vitro experiments revealed that hepcidin enhanced IFNg‐induced reactive oxygen species production and cytotoxicity in A549 cells. Conclusion Advanced NSCLC patients with high hepcidin expression may derive greater benefit from anti‐PD‐1/PD‐L1 monotherapy. Our findings suggest that cellular sensitivity to IFNg varies by hepcidin expression levels.