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Background <p>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<sup>+</sup> T cell stress resilience in abscopal tumors.</p> Methods <p>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 <i>Sfrp2</i> deletion, single-cell RNA sequencing, immunostaining, flow cytometry, and fibroblast-T cell co-culture assays were used to examine the relationship between SFRP2, CD8<sup>+</sup> T cell apoptosis, and stress-response signaling. Statistical analyses included two-sided tests and multiple-comparison correction where appropriate.</p> Results <p>Here we show that radioimmunotherapy activates local tumor immunity and tumor-draining lymph node priming, but resistant distant tumors fail to maintain CD8<sup>+</sup> T cell accumulation. SFRP2 is enriched in fibroblast-like stromal compartments and is inversely associated with CD8<sup>+</sup> T cell infiltration. Fibroblast-specific <i>Sfrp2</i> deletion reduces CD8<sup>+</sup> T cell apoptosis and restores an HSPA1A/HSP70-associated stress-resilience program. Mechanistically, SFRP2 suppresses a WNT-HSF1-HSPA1A signaling program, whereas <i>Hspa1a</i> overexpression reduces SFRP2-associated caspase-3 activation in T cells.</p> Conclusions <p>These findings identify stromal suppression of CD8<sup>+</sup> T cell stress resilience as a mechanism of abscopal resistance and support SFRP2-WNT-HSF1 pathway targeting as a potential strategy to improve radioimmunotherapy.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月28日

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  • Yu-Jie Zeng,
  • Kui-Mao Zhuang,
  • Pei-Shuang Xu,
  • Min-Jie Ruan,
  • Le-Yi Lin,
  • Ze-Qin Guo,
  • Zi-Xuan Rong,
  • Zhao-Guo Liu,
  • Zhong-Yi Dong,
  • Yan-Pei Zhang

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.