A Self-Amplifying Photodynamic Biomedicine for Cascade Immune Activation Against Triple-Negative Breast Cancer

Abstract

The efficacy of immunotherapy in triple-negative breast cancer (TNBC) is significantly hindered by its low immunogenicity and immunosuppressive tumor microenvironment. Non-invasive photodynamic therapy (PDT) is increasingly recognized as a potential immunotherapeutic stimulant in the treatment of TNBC. However, photodynamic immunotherapy is constrained by tumor hypoxia and excessive inflammation suppression during the course of treatment. Herein, a simple and efficacious biomedicine is formulated to overcome adverse influences by amplifying photodynamic immunotherapy, thereby stimulating the systemic immune response. Specifically, the approach targeted tumor delivery by employing specific agents such as the photosensitizer (verteporfin), the hypoxic ameliorator (atovaquone), and the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) signaling blocker (celecoxib). More importantly, the biomedicine effectively ameliorated hypoxia and inhibited COX-2/PGE2 signaling, thereby amplifying PDT-induced immunogenic cell death. This, in turn, enhanced the efficacy of photodynamic immunotherapy and triggered a robust immune response cascade. Notably, the self-amplifying photodynamic biomedicine significantly inhibited primary tumors, distal tumors, lung metastases, and post-operative recurrence while maintaining high biocompatibility. To sum up, the work provides a viable cascade stimulation approach and an efficient biomedical nanoplatform, offering a novel strategy for photodynamic immunotherapy of TNBC in the clinic.