肝癌中N1-乙酰亚精胺的外排促进巨噬细胞介导的免疫抑制，从而降低免疫治疗效果，这一成果由中山大学邝栋明研究小组经过不懈努力而取得。该研究于2025年6月2日发表于国际一流学术期刊《免疫学》杂志上。

该课题组研究人员研究了肝细胞癌（HCC）的代谢谱，这是一种对免疫检查点阻断（ICB）反应较差的疾病。HCC样本中多胺代谢增加。在多胺谱分析中，与非肿瘤肝组织相比，N1-乙酰亚精胺（N1-Ac-Spd）在HCC组织中积累，并且在配对血浆中升高。在临床前模型中，注射N1-Ac-Spd促进肿瘤进展，降低ICB的疗效。炎性巨噬细胞增加肝癌细胞中亚精胺/精胺N1-乙酰转移酶1 （SAT1）的表达，导致N1-Ac-Spd通过多胺转运蛋白SLC3A2外排增加。在机制上，N1-Ac-Spd外排以电荷依赖的方式激活SRC信号，进而诱导CCL1⁺巨噬细胞极化、CCR8⁺调节性T细胞募集和免疫抑制肿瘤微环境（TME）。针对SLC3A2、SAT1或CCL1的体内干预增强了ICB治疗的抗肿瘤作用。他们的发现为代谢重编程促进免疫抑制性TME的机制提供了见解，对HCC的治疗具有启示意义。

据介绍，代谢重编程是肿瘤进展的标志。

附：英文原文

Title: Efflux of N1-acetylspermidine from hepatoma fosters macrophage-mediated immune suppression to dampen immunotherapeutic efficacy

Author: Zheng-Yu Liu, Cai-Yuan Wu, Rui-Qi Wu, Jun-Cheng Wang, Chun-Xiang Huang, Xu-Yan Wang, Yaojun Zhang, Limin Zheng, Yun Chen, Xiang-Ming Lao, Dong-Ping Chen, Dong-Ming Kuang

Issue&Volume: 2025-06-02

Abstract: Metabolic reprogramming is a hallmark of tumor progression. Here, we examined the metabolic profile of hepatocellular carcinoma (HCC), a disease that responds poorly to immune checkpoint blockade (ICB). Polyamine metabolism increased in HCC samples. Of the polyamine spectrum analyzed, N1-acetylspermidine (N1-Ac-Spd) accumulated in HCC tissue as compared with nontumoral liver tissue and was elevated in paired plasma. Injection of N1-Ac-Spd promoted tumor progression in preclinical models and compromised the efficacy of ICB. Inflammatory macrophages increased expression of the spermidine/spermine N1-acetyltransferase 1, SAT1, in hepatoma cells, leading to increased N1-Ac-Spd efflux via the polyamine transporter protein SLC3A2. Mechanistically, N1-Ac-Spd efflux activated SRC signaling in a charge-dependent manner, which in turn induced CCL1+ macrophage polarization, the recruitment of CCR8+ regulatory T cells, and an immunosuppressive tumor microenvironment (TME). In vivo interventions targeting SLC3A2, SAT1, or CCL1 enhanced the antitumor effects of ICB therapy. Our findings provide insight into the mechanisms whereby metabolic reprogramming fosters an immunosuppressive TME, with implications for the treatment of HCC.

DOI: 10.1016/j.immuni.2025.05.006

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00227-4