中国南方医科大学Zhong-Yi Dong研究团队揭示了pai -1驱动的sfrp2高癌相关成纤维细胞劫持放射免疫治疗的体外效应。该项研究成果发表在2025年3月13日出版的《癌细胞》上。

放射免疫治疗的体外效应，即肿瘤缩小发生在放疗区之外，在治疗上是有希望的，但在临床上很少见。这种效应背后的机制尚不清楚。体内全基因组CRISPR筛选鉴定出SFRP2是体外效应的潜在基质调节因子。在未照射的肿瘤中，SFRP2表现出癌症相关成纤维细胞（CAF）特异性表达和放射免疫治疗介导的上调。CAFs中条件性的strp2基因敲除通过重新连接血管免疫微环境来促进CD8+ T细胞募集到未照射的肿瘤，从而增强了体外效应。体内谱系追踪显示，升高的SFRP2与放射免疫治疗驱动的周细胞谱系承诺相关。血清蛋白质组学显示，照射后的肿瘤分泌的PAI-1通过LRP1/p65轴触发远处肿瘤周细胞向高sfrp2 cas的转变。药理学阻断SFRP2或PAI-1可增强人源异种移植模型的体外作用。他们的研究结果共同阐明了pai -1诱导的高sfrp2 caf作为关键的基质调节剂来劫持体外效应，为提高放射免疫治疗的有效性提供了有希望的靶点。

Title: PAI-1-driven SFRP2high cancer-associated fibroblasts hijack the abscopal effect of radioimmunotherapy

Author: Yan-Pei Zhang, Ze-Qin Guo, Xiao-Ting Cai, Zi-Xuan Rong, Yuan Fang, Jia-Qi Chen, Kui-Mao Zhuang, Min-Jie Ruan, Si-Cong Ma, Le-Yi Lin, Duan-Duan Han, Yang-Si Li, Yuan-Yuan Wang, Jian Wang, Chuan-Hui Cao, Xin-Ran Tang, Qian-Kun Xie, Yue Chen, Yan Lin, Jia-Le Tan, Zi-Hang Yu, Ze-Nan Wu, Wei Wei, Da-Yong Zheng, Yu-Jie Zeng, Ying-Chen Ruan, Zi-Peng Xu, Jun-Zi Gu, Lu-Shan Xiao, Li Liu, Jian Guan, Xue Bai, De-Hua Wu, Zhong-Yi Dong

Issue&Volume: 2025-03-13

Abstract: The abscopal effect of radioimmunotherapy, wherein tumor shrinkage occurs beyond the irradiated field, is therapeutically promising but clinically rare. The mechanisms underlying this effect remain elusive. Here, in vivo genome-wide CRISPR screening identifies SFRP2 as a potential stromal regulator of the abscopal effect. SFRP2 exhibits cancer-associated fibroblast (CAF)-specific expression and radioimmunotherapy-mediated upregulation in unirradiated tumors. Conditional Sfrp2 knockout in CAFs boosts the abscopal effect by rewiring the vascular-immune microenvironment to promote CD8+ T cell recruitment to unirradiated tumors. In vivo lineage tracing reveals that elevated SFRP2 correlates with radioimmunotherapy-driven pericyte lineage commitment. Serum proteomics reveals that irradiated-tumor-secreted PAI-1 triggers distant tumor pericyte cell-fate transition into SFRP2high CAFs via the LRP1/p65 axis. Pharmacologically blocking SFRP2 or PAI-1 enhances the abscopal effect in humanized patient-derived xenograft models. Our findings collectively illustrate that PAI-1-induced SFRP2high CAFs serve as critical stromal regulator to hijack the abscopal effect, providing promising targets for enhancing radioimmunotherapy effectiveness.

DOI: 10.1016/j.ccell.2025.02.024

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00076-5