Radiation-activated astrocytes promote tumor progression through CXCL12 secretion and induce resistance to anti-PD-1...

Radiotherapy serves as the core component of comprehensive treatment for glioma. However, current clinical radiotherapy strategies fail to fully recognize the paracrine effects of irradiated stromal cells and their mediated therapeutic resistance, which has become a key factor limiting clinical outcomes of glioma. As stromal cells within the tumor microenvironment have gradually emerged as a critical research hotspot in oncology, this study focused on astrocytes to elucidate the novel molecular mechanism by which radiation-activated astrocytes facilitate the malignant progression of glioma and induce treatment failure.

Using in vitro co-culture systems, subcutaneous mouse models, and orthotopic mouse models, we investigated the paracrine effects of astrocytes exposed to 4 Gy radiation dose. The focus was on measuring CXCL12 secretion levels and analyzing their impact on the survival rates and radioresistance of irradiated glioma cells. Additionally, we compared the immunosuppressive microenvironment between recurrent gliomas post-radiotherapy and primary gliomas, evaluating their responsiveness to programmed cell death protein 1 (PD-1) antibody therapy.

Irradiated astrocytes secreted significantly higher levels of CXCL12, directly enhancing the survival of irradiated glioma cells and inducing radioresistance. Notably, the immunosuppressive microenvironment in recurrent gliomas after radiotherapy was more pronounced than in primary gliomas, leading to a markedly reduced response to PD-1 antibody therapy compared to primary tumors.

These findings suggest that immunotherapy should be prioritized for the treatment of primary tumors rather than being added to regimens for recurrent tumors, where it has already demonstrated poor therapeutic efficacy.