Abstract

Despite multiple therapeutic strategies have provided clinical benefit for certain subsets of non-small cell lung cancer (NSCLC) patients, achieving durable treatment responses remains a significant challenge. Immunotherapy has shown clinical benefits in lung cancer patients, while the efficacy is not quite satisfactory, especially in patients with lung adenocarcinoma (LUAD). Ferroptosis, a form of programmed cell death driven by iron-dependent lipid peroxidation, has recently emerged as a critical regulator of metabolic circuitry and anti-tumor immunity. Here, we identify BZW1 (Basic Leucine Zipper and W2 Domains 1) as a central regulator that promotes immune evasion through ferroptosis suppression in LUAD. Mechanistically, BZW1 attenuates ferroptosis via suppression of FTH1 degradation via autophagic degradation of NCOA4, the selective cargo receptor. Moreover, BZW1 competitively binds with NCOA4 and disrupts the binding of FTH1 and NCOA4, thus inhibiting ferritinophagy-mediated ferritin degradation.  BZW1 attenuates ferroptosis and creates an immunosuppressive microenvironment by reducing immunogenic cell death and impairing T cell activation. Our findings establish BZW1 as a ferroptosis suppressor whose inhibition may synergize with immunotherapy in LUAD, highlighting the therapeutic potential of targeting the BZW1-ferroptosis axis for lung cancer treatment.