PAI-1-driven SFRP2high cancer-associated fibroblasts hijack the abscopal effect of radioimmunotherapy PMID: 40086438

ADC Targets in Oncology

2026-04-10

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

Cancer Cell. 2025 Mar 12:S1535-6108(25)00076-5. doi: 10.1016/j.ccell.2025.02.024.

Yan-Pei Zhang ¹ , Ze-Qin Guo ¹ , Xiao-Ting Cai ¹ , Zi-Xuan Rong ¹ , Yuan Fang ¹ , Jia-Qi Chen ¹ , Kui-Mao Zhuang ¹ , Min-Jie Ruan ¹ , Si-Cong Ma ¹ , Le-Yi Lin ¹ , Duan-Duan Han ¹ , Yang-Si Li ² , Yuan-Yuan Wang ³ , Jian Wang ¹ , Chuan-Hui Cao ¹ , Xin-Ran Tang ¹ , Qian-Kun Xie ¹ , Yue Chen ¹ , Yan Lin ¹ , Jia-Le Tan ¹ , Zi-Hang Yu ¹ , Ze-Nan Wu ¹ , Wei Wei ⁴ , Da-Yong Zheng ⁵ , Yu-Jie Zeng ⁶ , Ying-Chen Ruan ¹ , Zi-Peng Xu ¹ , Jun-Zi Gu ¹ , Lu-Shan Xiao ⁷ , Li Liu ⁸ , Jian Guan ⁹ , Xue Bai ¹⁰ , De-Hua Wu ¹¹ , Zhong-Yi Dong ¹²

Affiliations

1. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
2. Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510515, Guangdong, China.
3. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
4. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Oncology, Xiangyang Central Hospital, Hubei University of Arts and Science, Xiangyang, Hubei 441000, China.
5. Department of Oncology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde Foshan), Shunde 528333, China.
6. Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China.
7. Big Data Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
8. Big Data Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Health Management Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
9. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
10. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
11. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].
12. Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: [email protected].

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 SFRP2^high 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 SFRP2^high CAFs serve as critical stromal regulator to hijack the abscopal effect, providing promising targets for enhancing radioimmunotherapy effectiveness.

Keywords

PAI-1; SFRP2; abscopal effect; cancer-associated fibroblasts; pericytes; radioimmunotherapy; stromal lineage.