Yang Hanshen, Zhang Xiaozhen, Zhang Sirui, Yang Yanqing, Chen Yan, Jiang Yangwei, Lu Qingsong, Liu Lingyue, Lao Mengyi, Du Weiran, Sun Kang, He Lihong, Shi Jiatao, Liu Xinyuan, Song Jinyuan, Lu Na, Huang Junming, Huang Jinyan, Zhou Ruhong, Lu Xiongbin, Liang Tingbo, Bai Xueli
Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Nat Commun. 2025 Aug 22;16(1):7827. doi: 10.1038/s41467-025-63146-2.
While dysregulation of polyamine metabolism is frequently observed in cancer, it is unknown how polyamines alter the tumor microenvironment (TME) and contribute to therapeutic resistance. Analysis of polyamines in the plasma of pancreatic cancer patients reveals that spermine levels are significantly elevated and correlate with poor prognosis. Using a multi-omics approach, we identify Serpinb9 as a vulnerability in spermine metabolism in pancreatic cancer. Serpinb9, a serine protease inhibitor, directly interacts with spermine synthase (SMS), impeding its lysosome-mediated degradation and thereby augmenting spermine production and secretion. Mechanistically, the accumulation of spermine in the TME alters the metabolic landscape of immune cells, promoting CD8 T cell dysfunction and pro-tumor polarization of macrophages, thus creating an immunosuppressive microenvironment. Small peptides that disrupt the Serpinb9-SMS interaction significantly enhance the efficacy of immune checkpoint blockade therapy. Together, our findings suggest that targeting spermine metabolism is a promising strategy to improve pancreatic cancer immunotherapy.
虽然在癌症中经常观察到多胺代谢失调，但尚不清楚多胺如何改变肿瘤微环境（TME）并导致治疗耐药性。对胰腺癌患者血浆中的多胺进行分析发现，精胺水平显著升高且与预后不良相关。通过多组学方法，我们确定丝氨酸蛋白酶抑制剂B9（Serpinb9）是胰腺癌精胺代谢中的一个薄弱环节。Serpinb9作为一种丝氨酸蛋白酶抑制剂，直接与精胺合酶（SMS）相互作用，阻碍其溶酶体介导的降解，从而增加精胺的产生和分泌。从机制上讲，TME中精胺的积累改变了免疫细胞的代谢格局，促进CD8 T细胞功能障碍和巨噬细胞的促肿瘤极化，从而形成免疫抑制微环境。破坏Serpinb9-SMS相互作用的小肽显著增强免疫检查点阻断疗法的疗效。总之，我们的研究结果表明，靶向精胺代谢是改善胰腺癌免疫治疗的一种有前景的策略。
