美国密歇根大学邹伟平课题组的一项最新研究开发出STAT5和STAT3的平衡影响树突状细胞功能和肿瘤免疫。相关论文于2025年5月14日发表于国际顶尖学术期刊《自然》杂志上。

在这里，该研究组发现ICB重编程树突状细胞中STAT3和STAT5转录途径之间的相互作用，从而激活T细胞免疫并使ICB有效。在机制上，STAT3抑制JAK2和STAT5的转录途径，决定树突状细胞功能的命运。由于STAT3经常在肿瘤微环境中被激活，研究小组开发了两种不同的STAT3 PROTAC（蛋白水解靶向嵌合体）降解物SD-36和SD-2301。STAT3降解物有效地降解树突状细胞中的STAT3，并重新编程树突状细胞转录网络，使其具有免疫原性。

此外，STAT3降解物单药治疗小鼠晚期肿瘤和ICB耐药肿瘤均有效，且无毒性。因此，STAT3和STAT5转录途径之间的相互作用决定了肿瘤微环境中的树突状细胞表型，STAT3降解物有望用于癌症免疫治疗。

研究人员表示，免疫检查点阻断（ICB）已经改变了癌症治疗。免疫治疗的效果取决于树突状细胞介导的肿瘤抗原呈递、T细胞启动和激活。然而，树突状细胞中的关键转录因子与ICB疗效之间的关系尚不清楚。

附：英文原文

Title: STAT5 and STAT3 balance shapes dendritic cell function and tumour immunity

Author: Zhou, Jiajia, Tison, Kole, Zhou, Haibin, Bai, Longchuan, Acharyya, Ranjan Kumar, McEachern, Donna, Metwally, Hoda, Wang, Yu, Pitter, Michael, Choi, Jae Eun, Vatan, Linda, Liao, Peng, Yu, Jiali, Lin, Heng, Jiang, Long, Wei, Shuang, Gao, Xue, Grove, Sara, Parolia, Abhijit, Cieslik, Marcin, Kryczek, Ilona, Green, Michael D., Lin, Jian-Xin, Chinnaiyan, Arul M., Leonard, Warren J., Wang, Shaomeng, Zou, Weiping

Issue&Volume: 2025-05-14

Abstract: Immune checkpoint blockade (ICB) has transformed cancer therapy1,2. The efficacy of immunotherapy depends on dendritic cell-mediated tumour antigen presentation, T cell priming and activation3,4. However, the relationship between the key transcription factors in dendritic cells and ICB efficacy remains unknown. Here we found that ICB reprograms the interplay between the STAT3 and STAT5 transcriptional pathways in dendritic cells, thereby activating T cell immunity and enabling ICB efficacy. Mechanistically, STAT3 restrained the JAK2 and STAT5 transcriptional pathway, determining the fate of dendritic cell function. As STAT3 is often activated in the tumour microenvironment5, we developed two distinct PROTAC (proteolysis-targeting chimera) degraders of STAT3, SD-36 and SD-2301. STAT3 degraders effectively degraded STAT3 in dendritic cells and reprogrammed the dendritic cell–transcriptional network towards immunogenicity. Furthermore, STAT3 degrader monotherapy was efficacious in treatment of advanced tumours and ICB-resistant tumours without toxicity in mice. Thus, the crosstalk between STAT3 and STAT5 transcriptional pathways determines the dendritic cell phenotype in the tumour microenvironment and STAT3 degraders hold promise for cancer immunotherapy.

DOI: 10.1038/s41586-025-09000-3

Source: https://www.nature.com/articles/s41586-025-09000-3