| First Author | Zhang YP | Year | 2025 |
| Journal | Cancer Cell | Volume | 43 |
| Issue | 5 | Pages | 856-874.e9 |
| PubMed ID | 40086438 | Mgi Jnum | J:386352 |
| Mgi Id | MGI:8203618 | Doi | 10.1016/j.ccell.2025.02.024 |
| Citation | Zhang YP, et al. (2025) PAI-1-driven SFRP2(high) cancer-associated fibroblasts hijack the abscopal effect of radioimmunotherapy. Cancer Cell 43(5):856-874.e9 |
| abstractText | 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. |
