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.

脂质代谢在肿瘤进展与免疫逃逸中发挥关键作用。靶向脂肪酸氧化（Fatty Acid Oxidation, FAO）已被证实是颇具潜力的癌症治疗策略。然而，脂肪酸氧化抑制对肿瘤免疫微环境的影响仍未得到充分阐明。本研究发现，通过靶向CPT1A抑制脂肪酸氧化，可通过诱导线粒体DNA胞质渗漏，显著激活cGAS/STING通路。这一过程会招募中性粒细胞浸润肿瘤，并激活特定亚群中性粒细胞的抗肿瘤功能，该亚群在抑制肿瘤生长中发挥关键作用。本研究结果表明，CPT1A可作为三阴性乳腺癌（Triple-Negative Breast Cancer, TNBC）治疗的潜在靶点；此外，本研究还揭示了中性粒细胞在cGAS/STING通路激活后所具备的核心抗肿瘤功能。实验整体设计：使用CD8抗体仅能有限延缓Cpt1a缺失诱导的肿瘤消退，提示在Cpt1a缺失的肿瘤微环境中，其他未知免疫细胞也可能参与肿瘤清除。因此，我们对4T1肿瘤样本进行了单细胞RNA测序（Single-Cell RNA Sequencing, scRNA-seq），以解析Cpt1a缺失后肿瘤细胞组成的变化。