虽然抗程序性细胞死亡蛋白 1 (PD-1) 单一疗法已显示出治疗肺癌的有效性，但其缓解率仅限于 20% 左右。最近的研究表明，肺腺癌患者的脂质代谢异常可能会阻碍抗PD-1单药治疗的疗效。在这里，我们深入研究了癌症基因组图谱（TCGA）-肺腺癌（LUAD）患者的脂质代谢模式及其与肿瘤免疫微环境细胞浸润特征的相关性。此外，构建了脂质代谢评分（LMS）系统，并基于LMS系统进一步筛选潜在的脂质代谢靶向药物。利用RNA测序、共培养技术和体内实验进一步验证了MK1775的机制。我们开发了LSM系统并鉴定了一种潜在的敏化剂MK1775，它靶向脂质代谢并增强抗PD-1治疗的效果。我们的结果表明，MK1775 通过影响肿瘤细胞与肿瘤相关巨噬细胞和 CD8 T 细胞之间的脂质串扰来抑制肿瘤进展，从而提高抗 PD-1 治疗的有效性。此外，我们发现MK1775抑制磷脂酰肌醇3激酶（PI3K）/AKT/哺乳动物雷帕霉素靶点（mTOR）信号通路，一方面下调FASN介导的脂肪酸（FAs）合成，从而抑制肿瘤的脂肪酸氧化另一方面，相关巨噬细胞促进IRF介导的CXCL10和CXCL11分泌，以促进CD8 T细胞的浸润。这些发现强调了脂质代谢在塑造复杂的肿瘤微环境中的重要作用。通过操纵肿瘤微环境中错综复杂的脂质代谢，我们可以发现并开发有前景的策略来使免疫疗法敏感，从而可能彻底改变癌症治疗方法。©作者（或其雇主）2024。允许重复使用CC BY-NC。不得商业再利用。请参阅权利和权限。英国医学杂志出版。

While anti-programmed cell death protein-1 (PD-1) monotherapy has shown effectiveness in treating lung cancer, its response rate is limited to approximately 20%. Recent research suggests that abnormal lipid metabolism in patients with lung adenocarcinoma may hinder the efficacy of anti-PD-1 monotherapy.Here, we delved into the patterns of lipid metabolism in patients with The Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD) and their correlation with the immune microenvironment's cellular infiltration characteristics of the tumor. Furthermore, the lipid metabolism score (LMS) system was constructed, and based on the LMS system, we further performed screening for potential agents targeting lipid metabolism. The mechanism of MK1775 was further validated using RNA sequencing, co-culture technology, and in vivo experiments.We developed an LSM system and identified a potential sensitizing agent, MK1775, which targets lipid metabolism and enhances the effects of anti-PD-1 treatment. Our results demonstrate that MK1775 inhibits tumor progression by influencing lipid crosstalk between tumor cells and tumor-associated macrophages and CD8+T cells, thereby increasing the effectiveness of anti-PD-1 treatment. Further, we found that MK1775 inhibited the phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway, which on one hand downregulated FASN-mediated synthesis of fatty acids (FAs) to inhibit fatty acid oxidation of tumor-associated macrophages, and on the other hand, promoted IRF-mediated secretion of CXCL10 and CXCL11 to facilitate the infiltration of CD8+ T cells.These findings emphasize the important role of lipid metabolism in shaping the complex tumor microenvironment. By manipulating the intricate intricacies of lipid metabolism within the tumor microenvironment, we can uncover and develop promising strategies to sensitize immunotherapy, potentially revolutionizing cancer treatment approaches.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.