Tumor cell-specific Gpx4 deficiency reshaps tumor microenvironment and promotes NSCLC progression.

Knockout or inhibition of glutathione peroxidase 4 (GPX4) induces ferroptosis which has been proposed as a potential therapeutic strategy for cancer. Here we unexpectedly found that inducible knockout of GPX4 in tumor cells significantly promotes non-small cell lung cancer (NSCLC) progression in the autochthonous KrasLSL-G12D/+Lkb1fl/fl (KL) and KrasLSL-G12D/+Tp53fl/fl (KP) mouse models, whereas inducible overexpression of GPX4 in tumor cells had an opposite effect. Mechanistically, knockout of GPX4 in tumor cells results in the accumulation of triacylglycerol (TAG) that was stored in lipid droplets in tumor cells and the efflux of TAG that induces ferroptosis of macrophages in the tumor microenvironment (TME), thereby igniting an immunoinhibitory TME characterized by the dysfunction of anti-tumor T cells and the decrease of antigen-presenting macrophages. Consistently, treatment with liprostatin-1 or inducible overexpression of GPX4 in tumor cells significantly rescues the ferroptosis of macrophages and ignites the activation of T cells in the TME, thereby inhibiting NSCLC progression. These findings highlight a previously uncharacterized role of tumor cell-specific GPX4 in NSCLC progression by modulating TAG metabolism in the TME and provide potential therapeutic strategies for NSCLC. Comparative gene expression profiling analysis of single cell RNA-seq data in immune cells sorted from tumor-burdened lungs of KrasLSL-G12D/+Tp53fl/flIL8 mice.