Restoration of CD8+ T cell stress resilience and abscopal effect of radioimmunotherapy via SFRP2-WNT-HSF1 pathway targeting

The abscopal effect, in which radiotherapy of one tumor is associated with regression of distant non-irradiated tumors, remains uncommon even when combined with immune checkpoint blockade. Although systemic T cell priming is required, the mechanisms that determine whether effector T cells persist within distant tumors remain unclear. We investigated whether SFRP2-expressing stromal cells limit CD8+ T cell stress resilience in abscopal tumors. We used bilateral mouse tumor models treated with fractionated radiotherapy plus anti-PD-1 antibody, combined with immune profiling of irradiated tumors, tumor-draining lymph nodes, and distant tumors. Human lung cancer specimens, public transcriptomic datasets, fibroblast-specific Sfrp2 deletion, single-cell RNA sequencing, immunostaining, flow cytometry, and fibroblast-T cell co-culture assays were used to examine the relationship between SFRP2, CD8+ T cell apoptosis, and stress-response signaling. Statistical analyses included two-sided tests and multiple-comparison correction where appropriate. Here we show that radioimmunotherapy activates local tumor immunity and tumor-draining lymph node priming, but resistant distant tumors fail to maintain CD8+ T cell accumulation. SFRP2 is enriched in fibroblast-like stromal compartments and is inversely associated with CD8+ T cell infiltration. Fibroblast-specific Sfrp2 deletion reduces CD8+ T cell apoptosis and restores an HSPA1A/HSP70-associated stress-resilience program. Mechanistically, SFRP2 suppresses a WNT-HSF1-HSPA1A signaling program, whereas Hspa1a overexpression reduces SFRP2-associated caspase-3 activation in T cells. These findings identify stromal suppression of CD8+ T cell stress resilience as a mechanism of abscopal resistance and support SFRP2-WNT-HSF1 pathway targeting as a potential strategy to improve radioimmunotherapy. Doctors sometimes observe that when one tumor is treated with radiotherapy together with immunotherapy, tumors elsewhere in the body also shrink. This is called the abscopal effect, but it is uncommon and difficult to predict. In this study, we asked why this effect fails in some tumors even when tumor-fighting cells, called T cells, are successfully activated. Using mouse models, human lung cancer samples, and single-cell analyses, we found that a form of cells called cancer-associated fibroblasts can block this response. These cells produce SFRP2, a protein that weakens a stress-protection response in nearby tumor-fighting T cells and makes them more likely to die after reaching distant tumors. Our findings suggest that protecting T cells from this weakened state may help improve radioimmunotherapy. Zeng, Zhuang, Xu, Ruan, Lin et al. study resistance to radioimmunotherapy-induced abscopal responses. They show that SFRP2-expressing fibroblasts impair CD8 + T cell stress resilience and promote apoptosis in distant tumors.