GPAT4 regulates antitumor immune response through activating the mtDNA-cGAS axis in cancer cells.

Activating tumor-intrinsic innate immune pathways can promote tumor antigen presentation and immune cell recruitment, thereby improving the immunosuppressive microenvironment and overcoming resistance to immune checkpoint blockade (ICB). However, the specific molecular targets remain insufficiently defined. Bioinformatic analysis revealed that Glycerol-3-phosphate acyltransferase 4 (GPAT4) is highly expressed in various tumors, including pancreatic cancer and breast cancer, and is significantly associated with low immunogenicity, poor immune-cell infiltration, and unfavorable prognosis. Syngeneic C57BL/6J and BALB/c tumor-bearing experiments showed that Gpat4-deficient pancreatic and breast tumors grew more slowly and exhibited increased infiltration of CD8+ T lymphocytes and enhanced CD8+ T cell effector-marker expression. Mechanistic studies indicated that GPAT4 deficiency leads to mitochondrial stress and the release of mitochondrial DNA (mtDNA) into the cytoplasm, thereby activating the cyclic GMP-AMP synthase (cGAS) signaling pathway. Interestingly, this process is independent of the metabolic enzyme activity of GPAT4. Single-cell analysis of breast and pancreatic tumors revealed that tumors with low GPAT4 expression exhibit higher levels of interferon response pathway activity and greater infiltration of immune cells, particularly CD8+ T cells and natural killer (NK) cells, which directly mediate tumor killing. In conclusion, our study identifies GPAT4 as a critical innate immune checkpoint molecule in tumor cells. Targeting this molecule can activate tumor-intrinsic innate immune pathways, thereby enhancing antitumor immune responses.