Deciphering the CAF‑LCN2 axis: Key to overcoming anti‑PD‑L1 immunotherapy resistance in lung cancer

Lung cancer is a highly aggressive malignancy associated with a high global mortality rate. Immunotherapy, particularly anti‑programmed cell death protein 1 (PD‑1) therapy, has offered new hope for patients; however, therapeutic resistance remains a major obstacle to clinical success. In the present study, single‑cell RNA sequencing was utilized to investigate the molecular characteristics of lung cancer and to elucidate the mechanisms underlying resistance to anti‑PD‑1 immunotherapy. Cancer‑associated fibroblasts (CAFs) were identified as key contributors to immune resistance. Functional assays, including CCK‑8, EdU, TUNEL and Transwell experiments, demonstrated that CAFs regulated the expression of lipocalin 2 (LCN2) in lung cancer cells, and elevated LCN2 levels were found to promote resistance to immunotherapy, as well as to enhance cellular proliferation and invasion. The effects of LCN2 on tumor growth, invasion, immune infiltration and ferroptosis were further validated by molecular and histological analyses. The results showed that silencing LCN2 induced ferroptosis in lung cancer cells, resulting in increased sensitivity to anti‑PD‑1 therapy, suppressed tumor growth and reduced invasiveness. These findings highlight the critical role of the CAF‑LCN2 axis in mediating resistance to anti‑PD‑1 immunotherapy and suggest that targeting this pathway may represent a promising strategy to enhance treatment efficacy in lung cancer.