Targeted extracellular vesicle-photoimmunotherapy remodels stromal-immune microenvironment to boost chemo-immunotherapy in preclinical models

Summary Solid tumors, especially pancreatic ductal adenocarcinomas (PDACs), activate quiescent fibroblasts into cancer-associated fibroblasts (CAFs) that generate dense desmoplastic stroma. This barrier restricts drug penetration and immune infiltration, promoting tumor progression. Here, we engineer Midkine (MDK)-targeting nanobody-functionalized extracellular vesicles (D4-EV) as a precision photoimmunotherapy platform. These vesicles selectively accumulate in the tumor microenvironment through MDK overexpression. Loaded with chlorin e6 (Ce6), Ce6@D4-EV induces immunogenic cell death upon light irradiation, triggering dsDNA release and cGAS-STING activation in tumor-associated macrophages. Concurrently, it reprograms CAFs, reduces extracellular matrix deposition, improves vascular perfusion, and alleviates hypoxia. This stromal-immune remodeling substantially enhances the therapeutic efficacy of immune checkpoint blockade, adoptive T cell therapy, and chemotherapy, leading to prolonged survival in multiple MDK-positive preclinical tumor models. The platform provides a promising strategy to overcome stromal barriers in desmoplastic tumors.