Abstract：
Mortality rates due to lung cancer are high worldwide. Although PD-1 and PD-L1 immune checkpoint inhibitors boost the survival of patients with non-small-cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build-up and potential lysine-lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non-histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi-omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl-APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti-APOC2K70-lac antibody that sensitized anti-PD-1 therapy in vivo is developed. This findings highlight the potential of anti lactyl-APOC2-K70 approach as a new combination therapy for sensitizing immunotherapeutic responses.
摘要：
由于肺癌的死亡率在世界范围内很高。尽管PD-1和PD-L1免疫检查点抑制剂可以提高非小细胞肺癌（NSCLC）患者的生存率，抵抗经常出现。Warburg效应,这导致乳酸积累和潜在的赖氨酸-乳酸化（Kla），将免疫功能障碍与肿瘤代谢联系起来。非组蛋白Kla在肿瘤免疫微环境和免疫治疗中的作用尚待阐明。这里,我们对非小细胞肺癌患者的样本进行了整体的乳糜体谱分析和代谢组学分析.通过将多组学分析与体外和体内验证相结合，揭示了细胞内乳酸通过乳酰-APOC2促进细胞外脂解。机械上,乳酸在K70时增强APOC2的乳酸化，使其稳定并导致FFA释放，调节性T细胞积累，免疫疗法抗性，和转移。此外，开发了体内致敏抗PD-1治疗的抗APOC2K70-lac抗体。这一发现强调了抗乳酰-APOC2-K70方法作为一种新的联合疗法用于敏化免疫治疗反应的潜力。
