Abstract：
Immunomodulatory effects of long-chain fatty acids (LCFAs) and their activating enzyme, acyl-coenzyme A (CoA) synthetase long-chain family (ACSL), in the tumor microenvironment remain largely unknown. Here, we find that ACSL5 functions as an immune-dependent tumor suppressor. ACSL5 expression sensitizes tumors to PD-1 blockade therapy in vivo and the cytotoxicity mediated by CD8+ T cells in vitro via regulation of major histocompatibility complex class I (MHC-I)-mediated antigen presentation. Through screening potential substrates for ACSL5, we further identify that elaidic acid (EA), a trans LCFA that has long been considered harmful to human health, phenocopies to enhance MHC-I expression. EA supplementation can suppress tumor growth and sensitize PD-1 blockade therapy. Clinically, ACSL5 expression is positively associated with improved survival in patients with lung cancer, and plasma EA level is also predictive for immunotherapy efficiency. Our findings provide a foundation for enhancing immunotherapy through either targeting ACSL5 or metabolic reprogramming of antigen presentation via dietary EA supplementation.
摘要：
长链脂肪酸(LCFAs)及其激活酶的免疫调节作用,酰基辅酶A（CoA）合成酶长链家族（ACSL），肿瘤微环境在很大程度上仍然未知。这里,我们发现ACSL5具有免疫依赖性肿瘤抑制因子的功能。ACSL5表达通过调节主要组织相容性复合物I类（MHC-I）介导的抗原呈递使肿瘤体内对PD-1阻断治疗敏感，并在体外使CD8T细胞介导的细胞毒性敏感。通过筛选ACSL5的潜在底物，我们进一步确定反油酸(EA)，一种长期以来被认为对人体健康有害的反式LCFA，表型以增强MHC-I表达。EA补充可以抑制肿瘤生长并使PD-1阻断疗法敏感。临床上,ACSL5表达与肺癌患者生存率改善呈正相关，血浆EA水平也是免疫治疗效率的预测指标。我们的发现为通过饮食EA补充靶向ACSL5或抗原呈递的代谢重编程来增强免疫治疗提供了基础。
