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Compared with chemotherapy and radiotherapy that deplete lymph, photodynamic therapy (PDT) is a tumor treatment method that inherently stimulates the immune response by inducing immunogenic cell death (ICD). However, the immunosuppressive tumor microenvironment (TME) often weakens the immune response triggered by PDT, limiting its effectiveness in eliminating distant and metastatic tumor cells. Method: To maximize the immunotherapy effect of PDT, we developed a photodynamic immunotherapy liposome nanoplatform (PDIT-liposome), integrating components targeting the consecutive stages of anti-tumor immune response: 1) a phthalocyanine photosensitizer that induces ICD, 2) a factor Xa inhibitor (rivaroxaban) that promotes T cell activation, and 3) a programmed death ligand 1 inhibitor to enhance the attack of cytotoxic T lymphocytes (CTL). To achieve light-controlled drug release at the tumor site, the liposomes were constructed using phospholipids sensitive to reactive oxygen species to respond to the PDT effect. Results: PDIT liposomes were identified through multiple physical and chemical as well as optical evaluations. Comprehensive in vitro and in vivo studies confirmed that PDIT liposomes significantly enhanced anti-tumor efficacy compared to single treatment and combination treatments. In the subcutaneous engrafted tumor model, the anti-tumor rate of PDIT liposomes was 91.7%, while that of P-liposomes was 21.83%, PD-liposomes was 46.78%, and PR-liposomes was 51.08% (p < 0.001). Mechanism analysis showed that the maturation of dendritic cells in tumor-draining lymph nodes (TDLNs) was enhanced (CD11c+ cells increased by 8 times), T cell activation was promoted (CD8+ T cells increased by 2.3 times), and CTL-mediated cytotoxicity was enhanced (CD107a+ activated CTL increased by 5.4 times). It is noteworthy that the PDIT therapy can induce long-term immune memory and inhibit 90.68% of tumor recurrence and metastasis rates. Conclusion: This study proposes a strategy to enhance the immunotherapy efficacy of PDT by synergistically targeting different stages of the immune response with drugs. It also theoretically validates the synergistic effect of PDT, anticoagulation therapy, and immune checkpoint inhibition in cancer treatment. This study was published in Theranostics under the title "ROS-sensitive liposomal co-delivery of photosensitizer, factor Xa inhibitor, and PD-L1 blockade enhances photodynamic immunotherapy".
Reference Information:
DOI: 10.7150/thno.125408
