Disturbances in tumor cell metabolism reshape the tumor microenvironment (TME) and impair antitumor immunity, but the implicit mechanisms remain elusive. Here, we found that spermine synthase (SMS) was significantly upregulated in tumor cells, which correlated positively with the immunosuppressive microenvironment and predicted poor survival in hepatocellular carcinoma (HCC) patients. Via “subcutaneous” and “orthotopic” HCC syngeneic mouse models and a series of in vitro coculture experiments, we identified elevated SMS levels in HCC cells played a role in immune escape mainly through its metabolic product spermine, which induced M2 polarization of tumor-associated macrophages (TAMs) and subsequently corresponded with a decreased antitumor functionality of CD8⁺ T cells. Mechanistically, we discovered that spermine reprogrammed TAMs mainly by activating the PI3K-Akt-mTOR-S6K signaling pathway. Spermine inhibition in combination with immune checkpoint blockade effectively diminished tumor burden in vivo. Our results expand the understanding of the critical role of metabolites in regulating cancer progression and antitumor immunity and open new avenues for developing novel therapeutic strategies against HCC.

肿瘤细胞代谢的紊乱重塑了肿瘤微环境 （TME） 并损害了抗肿瘤免疫力，但隐含的机制仍然难以捉摸。在这里，我们发现精胺合酶 （SMS） 在肿瘤细胞中显著上调，这与免疫抑制微环境呈正相关，并预测肝细胞癌 （HCC） 患者的生存率差。通过“皮下”和“原位”HCC 同基因小鼠模型和一系列体外共培养实验，我们发现 HCC 细胞中升高的 SMS 水平主要通过其代谢产物精胺在免疫逃逸中发挥作用，精胺诱导肿瘤相关巨噬细胞 （TAM） 的 M2 极化，随后与 CD8⁺ 的抗肿瘤功能降低相对应T 细胞。从机制上讲，我们发现精胺主要通过激活 PI3K-Akt-mTOR-S6K 信号通路来重编程 TAM。精胺抑制联合免疫检查点阻断可有效减轻体内肿瘤负荷。我们的结果扩大了对代谢物在调节癌症进展和抗肿瘤免疫中关键作用的理解，并为开发针对 HCC 的新型治疗策略开辟了新的途径。