Tumor Cell GPX4 Dictates Triacylglycerol Metabolism for Ferroptosis Susceptibility and Immune Evasion of NSCLC

The ferroptosis regulator glutathione peroxidase 4 (GPX4) has long been viewed as a guardian against lipid peroxidation, with its inhibition heralded as a promising therapeutic strategy to trigger iron-dependent cancer cell death (Yang et al., 2014). This paradigm, largely built on studies in cultured cells and subcutaneous graft models, posits that GPX4 loss uniformly induces ferroptosis and suppresses tumor growth (Yang et al., 2014;Zou et al., 2020). However, in this issue of Protein & Cell, a study by Wang et al. demonstrates that in autochthonous non-small cell lung cancer (NSCLC) models, inducible knockout of GPX4 in transformed tumor cells does not result in ferroptosis but instead orchestrates a profound triacylglycerol (TAG) metabolic rewiring that promotes cancer progression by evading ferroptosis and suppressing CD8⁺ T cell immunity.