LOX-1 mediated lipid peroxidation leads to dysfunction of tumor infiltrating CD8+ T cells in ovarian cancer.

Abnormal lipid accumulation in the tumor microenvironment (TME) promotes lipid peroxidation in tumor-infiltrating CD8+T cells (CD8+TILs), driving their dysfunction and impairing antitumor immunity in ovarian cancer (OC). To elucidate the underlying immunosuppressive mechanisms, we integrated clinical specimens, mouse models, and in-vitro validation. Notably, CD8+TILs from OC patients exhibited pronounced lipid peroxidation signatures. Elevated oxidized low-density lipoprotein (oxLDL) levels were detected in ovarian tumor interstitial fluid (TIF), tumor mass-derived supernatants, and tissue sections, correlating with accelerated peroxidation phenotype in CD8+TILs. Bulk RNA sequencing and experimental validation revealed LOX-1 as the dominant oxLDL receptor in CD8+TILs, where its expression was positively correlated with peroxidation levels and negatively linked to PRF1, GZMB, and IFNG expression. In ID8 mouse OC models, LOX-1 expression and lipid peroxidation in CD8+TILs increased with tumor progression, and LOX-1-neutralizing antibody treatment partially reversed these changes and restored T-cell function. In vitro, LOX-1 blockade reduced oxLDL-induced lipid peroxidation, restored IFN-γ and GZMB production, and downregulated PD-1 expression, whereas LOX-1 overexpression exerted the opposite effects. Notably, the antioxidants, not ferroptosis inhibitors, restored CD8+T cell effector function by suppressing peroxidation. Mechanistically, oxLDL/LOX-1 signaling activated the transcription factor ELF3, which subsequently bound to the PDCD1 promoter to drive PD-1 expression. Together, this study demonstrates that in CD8+TILs, LOX-1-mediated uptake of oxLDL induced lipid peroxidation via oxidative stress and establish the oxLDL/LOX-1 axis as a pivotal pathway through which lipid peroxidation impairs CD8+TILs function in OC. Targeting LOX-1 or employing antioxidants restored the antitumor capacity of CD8+TILs, providing a mechanistic basis for metabolically modulating T cell-based cancer immunotherapy.