Nanocomposites integrating antigen release and presentation for treatment of sarcoma

Soft-tissue sarcomas present a significant clinical challenge owing to their high postoperative recurrence rates and poor responsiveness to radiotherapy and chemotherapy. The insufficient infiltration of immune cells into the tumor microenvironment further limits the efficacy of immunotherapy. Photodynamic therapy (PDT) can induce immunogenic cell death (ICD) in tumor cells by releasing tumor-associated antigens. These antigens can be used to activate dendritic cells (DCs) in vitro and extract DC vesicles. These vesicles can activate T cells in a more effective and specific manner, promoting their maturation and tumor infiltration, thereby achieving effective tumor immunotherapy. After delivering photosensitizers to the tumor site via nanocarriers, the tumor antigens generated in situ by PDT can further enhance tumor accumulation and the anti-tumor immune response of these T cells. Based on this rationale, we developed a cell membrane-based nanoplatform that integrates PDT and T cell activation. Nanoparticles were fabricated by coating indocyanine green-loaded mesoporous polydopamine nanoparticles with a hybrid membrane derived from DCs activated by PDT-released antigens and tumor cells (DTM-MI). In vitro, DTM-MI demonstrated efficient tumor cell targeting and laser irradiation, produced abundant reactive oxygen species (ROS), and induced tumor cell death and release of ICD-related molecules. DTM-MI selectively accumulated in tumors of tumor-bearing mice in vivo Combined with PD-L1 antibody and laser irradiation, DTM-MI significantly inhibited tumor growth while elevating serum levels of immune-related cytokines, confirming anti-tumor immune activation. Lymph nodes showed increased T-cell and CD8 + T-cell populations, and tumor sites exhibited enhanced CD8 + T-cell and cytotoxic T lymphocyte (CTL) infiltration. The dual targeting of tumor cells and T cells by DTM-MI coupled with DC membrane-mediated T-cell activation and homing to PDT-treated regions facilitated potent tumor killing. Laser-triggered immunogenic cell death and antigen release further amplify T cell-mediated anti-tumor immunity, presenting a promising therapeutic approach for sarcomas.