Tumor cell-specific loss of GPX4 reprograms triacylglycerol metabolism to escape ferroptosis and impair antitumor immunity in NSCLC

Lung cancer is the leading cause of cancer-related mortality worldwide. Elucidating the molecular programs that enable tumor cells to evade regulated cell death and anti-tumor immune responses is essential for developing effective therapeutic strategies. In this study, Wang and colleagues employ a series of genetically engineered non-small cell lung cancer mouse models, high-throughput lipidomics assays, and functional perturbation experiments to uncover how tumor cells adapt metabolically to escape ferroptosis and reprogram the tumor microenvironment for CD8⁺ T cell dysfunction.

Their work reveals that tumor cell-specific loss of GPX4, a central antioxidant enzyme protecting cells from ferroptosis, promotes the progression of the autochthonous non-small cell lung cancer, rather than triggering ferroptotic death of tumor cells. Mechanistically, the established lung tumors acquire a ferroptosis-resistant state through triacylglycerol and oxidized triacylglycerol synthesis and lipid droplet accumulation. In addition, the tumor cells secrete triacylglycerol and oxidized triacylglycerol into the tumor microenvironment, leading to dysfunction of anti-tumor CD8⁺ T cells. Inhibition of triacylglycerol synthesis sensitizes tumor cells to ferroptosis and restores the function of CD8⁺ T cells, thereby inhibiting the progression of non-small cell lung cancer in mice.

The Editorial Office congratulates the authors for their rigorous experimentation and insightful interpretation, which together advance our understanding of redox biology and tumor evolution. The findings presented in this work may inspire new therapeutic strategies aimed at restoring ferroptotic vulnerability and CD8⁺ T cell function in resistant tumors, offering promising avenues for future translational research.

In this study, Wang et al. have characterized a tumor-cell-specific GPX4-(ox)TAG axis that evades ferroptosis and remodels the tumor microenvironment, and thereby promotes the pro