肿瘤细胞治疗研究
英文原题：Targeted extracellular vesicle-photoimmunotherapy remodels stromal-immune microenvironment to boost chemo-immunotherapy in preclinical models.
实体瘤，尤其是胰腺导管腺癌（PDAC），会激活静止的成纤维细胞转化为癌症相关成纤维细胞（CAF），从而生成致密的促结缔组织增生性基质。
实体瘤，尤其是胰腺导管腺癌（PDAC），会激活静息成纤维细胞转化为癌症相关成纤维细胞（CAF），从而生成致密的促结缔组织增生性基质。这一屏障限制了药物渗透和免疫浸润，促进肿瘤进展。在此，我们工程化改造了靶向中期因子（MDK）的纳米抗体功能化细胞外囊泡（D4-EV），作为精准光免疫治疗平台。这些囊泡通过MDK过表达选择性积聚于肿瘤微环境。负载二氢卟吩e6（Ce6）后，Ce6@D4-EV在光照下诱导免疫原性细胞死亡，触发dsDNA释放及肿瘤相关巨噬细胞中的cGAS-STING激活。同时，它重编程CAF，减少细胞外基质沉积，改善血管灌注，并缓解缺氧。这种基质-免疫重塑显著增强了免疫检查点阻断、过继性T细胞治疗和化疗的疗效，在多个MDK阳性临床前肿瘤模型中延长了生存期。该平台为克服促结缔组织增生性肿瘤中的基质屏障提供了一种有前景的策略。
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.
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