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.

长链脂肪酸 (LCFA) 及其激活酶酰基辅酶 A (CoA) 合成酶长链家族 (ACSL) 在肿瘤微环境中的免疫调节作用仍然很大程度上未知。在这里，我们发现 ACSL5 作为免疫依赖性肿瘤抑制因子发挥作用。 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，使肿瘤对体内PD-1 阻断疗法和体外CD8 ⁺ T 细胞介导的细胞毒性敏感。通过筛选 ACSL5 的潜在底物，我们进一步鉴定了反油酸 (EA)（一种长期以来被认为对人类健康有害的反式LCFA）可增强 MHC-I 表达的表型。补充 EA 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的提高呈正相关，血浆 EA 水平也可预测免疫治疗的效率。我们的研究结果为通过靶向 ACSL5 或通过膳食 EA 补充剂对抗原呈递进行代谢重编程来增强免疫治疗奠定了基础。