Targeting CPT1A triggers cGAS/STING activation to engage neutrophils for tumor elimination
Lipid metabolism plays an important role in tumor progression and immune evasion. Targeting fatty acid oxidation (FAO) has been shown to be a promising approach to treat cancers. However, the impact of FAO inhibition on tumor immune microenvironment is still less understood. In this study, we found that inhibiting FAO by targeting CPT1A dramatically triggers cGAS/STING activation through inducing cytoplasmic leakage of mitochondrial DNA. This leads to the infiltration of neutrophils into tumors and drive anti-tumor effects of a subset of neutrophils, which plays a crucial role in inhibiting tumor growth. Our current findings suggest that CPT1A could be a promising target for TNBC therapy and, moreover, we uncover an essential anti-tumor role of neutrophils upon cGAS/STING activation. Overall design: Using CD8 antibody had a limited effect on impeding the tumor regression induced by Cpt1a depletion, suggesting that other unknown immune cells may also contribute to tumor clearance in the context of Cpt1a deficiency.Thus, we conducted single-cell RNA sequencing (scRNA-seq) on the 4T1 tumor samples to dissect the alterations in cellular composition upon Cpt1a depletion.