Cancer Research · asia
Keeping T Cells Going in Distant Tumors: The SFRP2 Pathway Reveals a New Barrier to Radioimmunotherapy
Although radiotherapy may trigger a systemic immune response, unirradiated tumors often escape attack. A new study spanning mouse models, human lung cancer specimens, and single-cell analysis points to cancer-associated fibroblasts that secrete SFRP2.
When radiation is directed at one tumor, another unirradiated tumor also shrinks. This rare “abscopal effect” has long been a promising phenomenon in cancer treatment, yet one that is difficult to reproduce consistently. A study published in *Communications Medicine* suggests that the issue may lie not only in whether the immune system can mount an attack, but also in whether CD8-positive T cells that reach distant tumors can withstand stress and survive.
Yu-Jie Zeng, Kui-Mao Zhuang, Yan-Pei Zhang, and colleagues used bilateral mouse tumor models, administering fractionated radiotherapy to one side in combination with an anti-PD-1 antibody, and then comparing immune changes in the irradiated tumor, tumor-draining lymph nodes, and distant tumors. The results showed that the treatment could indeed initiate a local immune response and promote T-cell activation in the lymph nodes. However, in resistant distant tumors, CD8-positive T cells failed to continue accumulating.
The study traced this point of failure to the tumor stroma. Single-cell RNA sequencing, immunostaining, and analysis of human lung cancer specimens showed that SFRP2 was primarily enriched in fibroblast-like stromal regions, and that higher SFRP2 signaling was generally associated with less CD8-positive T-cell infiltration. Cell co-culture experiments further supported a mechanism in which SFRP2 secreted by fibroblasts weakens stress-protective responses in nearby T cells, making them more likely to initiate apoptosis.
The key pathway involves WNT, the heat shock factor HSF1, and the stress-response protein HSPA1A/HSP70. After the research team specifically deleted Sfrp2 in mouse fibroblasts, CD8-positive T-cell apoptosis decreased in distant tumors, and the associated stress-resilience program was reactivated. In cell experiments, increasing Hspa1a expression reduced SFRP2-associated caspase-3 activation. These results distinguish “T cells reaching the tumor” from “T cells surviving long enough within the tumor” as two separate barriers.
The finding also offers another direction for strategies combining radiotherapy with immune checkpoint inhibitors. Current combinations largely focus on increasing tumor antigen release or relieving T-cell suppression. If the SFRP2—WNT—HSF1 axis is indeed a survival barrier in distant tumors, future approaches may involve modifying fibroblast signaling and restoring T-cell stress responses to sustain abscopal responses for longer.
However, the evidence still consists mainly of mechanistic experiments in mice and correlative analyses of human lung cancer specimens. It has not yet been shown that blocking SFRP2 can improve treatment efficacy in patients, nor have a clinically suitable intervention method, dosage, and safety range been established. The paper is also currently an advance version that has yet to undergo further copyediting. Whether SFRP2 has consistent roles across different cancer types and normal tissues, and which patients have tumors truly driven by this pathway, still require further animal studies and prospective clinical validation.