Bispecific Antibody Targeting VEGF/TGF-β Synergizes with Local Radiotherapy: Turning Tumors from Cold to Inflamed and Amplifying Abscopal Effects.

Beyond inherently killing cancer cells by directly inducing double-strand DNA breaks, local radiotherapy (RT) can exert immune-priming effects and reprogram the tumor microenvironment (TME) from immune-cold tumors into inflamed, or "hot" tumors. Nevertheless, this immunogenic antitumor response may be partially counterbalanced by the upregulation of vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-β) induced by RT. Y332D, a bispecific antibody that simultaneously blockades VEGF and TGF-β, effectively synergized with RT, leading to a durable antitumor effect. Mechanistically, Y332D counteracted negative RT effects that are attributed to the upregulation of TGF-β and VEGF-mediated epithelial-mesenchymal transition, extracellular matrix remodeling, aberrant angiogenesis, immunosuppression, and radioresistance, as well as further enhanced or complemented the positive effects of RT, such as cGAS-STING activation, immunogenic cell death, enhanced antigen presentation, increased T cell infiltration, and antiangiogenic effects, thereby reprograming the TME from immune "cold" to inflamed state and forming an effective in-situ vaccine that, beyond local tumor eradication, could potentiate antitumor immune response and regress preestablished abscopal metastases. Together, our results indicate that this combination strategy successfully overcame the negative effects caused by RT and augmented abscopal effects, extending the application of RT to the treatment of both local and metastatic disease.