Yang Nan, Li Xiaoxue, Huang Wenwen, Ji Gaili, Luo Wei, Jiang Faming, Zeng Hao, Chen Yali, Chen Yao, Qiao Lina, Chen Lu, Rafii Shahin, Wang Wei, Zheng Ai, Ding Bi-Sen, Cao Zhongwei
Key Lab of Birth Defects and Related Diseases of Women and Children of MOE, State Key Lab of Biotherapy, State Key Laboratory of Respiratory Health and Multimorbidity, West China School of Basic Medical Sciences & Forensic Medicine, West China Second University Hospital, Sichuan University, Chengdu, China.
Department of Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Nat Cell Biol. 2025 Sep 5. doi: 10.1038/s41556-025-01740-8.
Chemoresistance is the leading cause of cancer-related death. How chemotherapy subjugates the cellular crosstalk in the tumour microenvironment to cause chemoresistance remains to be defined. Here we find chemotherapy enables immunosuppressive SDF1 endothelial niche to evade immunosurveillance in ovarian and breast cancers. We integrated human patient data and mouse models to show that chemotherapy selectively activates PARP1-SDF1 axis in tumour endothelial cells (ECs). This angiocrine SDF1 interferes with antitumour interplay between CXCL10 macrophages and CXCR3CD8 T cells and promotes tumour progression in ovarian and breast cancers. Proteome-based screening revealed that endothelial PARP1 PARylates MLKL, a key necroptosis effector to upregulate angiocrine SDF1 in ECs. In sum, we identify PARylation-dependent necroptosis in tumour ECs as an important step in subverting the tumour microenvironment to evade immunosurveillance.
化疗耐药是癌症相关死亡的主要原因。化疗如何征服肿瘤微环境中的细胞间串扰从而导致化疗耐药仍有待明确。在此，我们发现化疗使免疫抑制性SDF1内皮小生境能够逃避卵巢癌和乳腺癌中的免疫监视。我们整合了人类患者数据和小鼠模型，以表明化疗选择性激活肿瘤内皮细胞（ECs）中的PARP1-SDF1轴。这种血管分泌的SDF1干扰CXCL10巨噬细胞和CXCR3 CD8 T细胞之间的抗肿瘤相互作用，并促进卵巢癌和乳腺癌的肿瘤进展。基于蛋白质组的筛选显示，内皮PARP1使关键坏死性凋亡效应因子MLKL发生聚腺苷酸化，从而上调ECs中血管分泌的SDF1。总之，我们确定肿瘤ECs中PARylation依赖性坏死性凋亡是颠覆肿瘤微环境以逃避免疫监视的重要一步。
