醋酸代谢是许多癌症中的一个重要代谢途径，由乙酰辅酶A合酶2（ACSS2）控制，该酶催化醋酸转化为乙酰辅酶A。虽然ACSS2在癌症中的代谢作用已有详细描述，但阻断肿瘤醋酸代谢对肿瘤微环境和抗肿瘤免疫的影响尚不清楚。我们证明，阻断ACSS2将癌细胞从醋酸消费者转变为醋酸生产者，从而释放醋酸供肿瘤浸润淋巴细胞作为燃料源。我们展示了醋酸补充物在代谢上增强T细胞效应功能和增殖。利用CRISPR-Cas9引导或小分子抑制剂靶向ACSS2能够促进抗肿瘤免疫反应，并提高临床前乳腺癌模型中化疗的疗效。我们提出了一个用于靶向癌症中醋酸代谢的范例，即ACSS2的抑制不仅能够干扰肿瘤细胞的代谢，还能增强抗肿瘤免疫。© 2023. 作者，由 Springer Nature America, Inc. 独家许可使用。

Acetate metabolism is an important metabolic pathway in many cancers and is controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of acetate to acetyl-CoA. While the metabolic role of ACSS2 in cancer is well described, the consequences of blocking tumor acetate metabolism on the tumor microenvironment and antitumor immunity are unknown. We demonstrate that blocking ACSS2, switches cancer cells from acetate consumers to producers of acetate thereby freeing acetate for tumor-infiltrating lymphocytes to use as a fuel source. We show that acetate supplementation metabolically bolsters T-cell effector functions and proliferation. Targeting ACSS2 with CRISPR-Cas9 guides or a small-molecule inhibitor promotes an antitumor immune response and enhances the efficacy of chemotherapy in preclinical breast cancer models. We propose a paradigm for targeting acetate metabolism in cancer in which inhibition of ACSS2 dually acts to impair tumor cell metabolism and potentiate antitumor immunity.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.