北京生命科学研究所邵峰小组宣布他们开发出胞质细菌受体ALPK1激动剂诱导抗肿瘤免疫。该研究于2025年12月10日发表于国际一流学术期刊《自然》杂志上。

在这里，该研究团队检测了α-激酶1 （ALPK1）受体对细菌ADP-庚糖（ADP-Hep）的抗肿瘤功能。ADP-Hep处理小鼠可诱导多种促炎因子，包括CXCL10和CCL2，并刺激ALPK1依赖性抗肿瘤免疫。携带功能获得型ALPK1（T237M）疾病变异体的小鼠也排斥移植肿瘤。利用药物化学，该课题组发现了一种更有效的类似物，UDSP-Hep。与ADP-Hep相反，UDSP-Hep区分了ALPK1多态性，这与小鼠对细菌相关性结肠炎的易感性相关。

UDSP-Hep表现出更强的ALPK1介导的抗肿瘤作用，并与检查点抑制剂协同作用。这种作用需要CD8⁺ T细胞、树突状细胞（DC）和巨噬细胞，并且对阻断CXCL10或CCL2功能的抗体敏感。ALPK1激动剂激活DC交叉呈递，促进肿瘤特异性T细胞在肿瘤引流淋巴结中的扩增。ALPK1在具有明显炎症特征的非免疫细胞中比STING表达更广泛。UDSP-Hep在刺激肿瘤细胞抗原呈递、巨噬细胞-DC交叉启动和保护性记忆T细胞分化方面与STING激动剂不同，它不诱导T细胞凋亡。他们的研究阐明了ALPK1激动剂的抗肿瘤作用，并提示了ALPK1激动剂在癌症免疫治疗中的潜力。

研究人员表示，靶向先天免疫在癌症免疫治疗中具有前景，特别是在改善检查点抑制剂方面。然而，有前途的先天受体TLRs和STING的激动剂主题正面临挑战。

附：英文原文

Title: Agonists for cytosolic bacterial receptor ALPK1 induce antitumour immunity

Author: Tian, Xiaoying, Liu, Jiaqi, Li, Yuxi, Wang, Yupeng, Luo, Yuanhanyu, He, Huabin, She, Yang, Ma, Yan, Ding, Jingjin, Zhou, Ping, Li, Chao, Shao, Feng

Issue&Volume: 2025-12-10

Abstract: Targeting innate immunity holds promise in cancer immunotherapy, particularly in improving checkpoint inhibitors. However, the use of agonists of the promising innate receptors TLRs and STING1,2,3,4 is facing challenges. Here we examined the antitumour function of the α-kinase 1 (ALPK1) receptor for bacterial ADP-heptose (ADP-Hep)5,6,7. Treatment of mice with ADP-Hep induced multiple proinflammatory factors including CXCL10 and CCL2, and stimulated Alpk1-dependent antitumour immunity. Mice bearing a gain-of-function ALPK1(T237M) disease variant8 also rejected grafted tumours. Using medicinal chemistry, we identified a more potent analogue, UDSP-Hep. In contrast to ADP-Hep, UDSP-Hep distinguished Alpk1 polymorphism, which correlates with mouse susceptibility to bacteria-associated colitis9,10,11,12. UDSP-Hep exhibited a stronger Alpk1-mediated antitumour effect and synergized with checkpoint inhibitors. The effect required CD8+ T cells, dendritic cells (DCs) and macrophages, and was sensitive to antibodies that block CXCL10 or CCL2 function. ALPK1 agonists activated DCs for cross-presentation, promoting tumour-specific T cell expansion in the tumour-draining lymph nodes. ALPK1 has wider expression than STING in non-immune cells with a distinct inflammatory signature. UDSP-Hep is differentiated from STING agonists in stimulating tumour-cell antigen presentation, macrophage–DC cross-priming and protective memory T cell differentiation, and it does not induce T cell apoptosis. Our study elucidates the antitumour effect of ALPK1 agonism and suggests the potential of ALPK1 agonists in cancer immunotherapy.

DOI: 10.1038/s41586-025-09828-9

Source: https://www.nature.com/articles/s41586-025-09828-9