Combination of Niclosamide with Immunogenic Cell Death-Inducer Delivered by Nanoparticles for Breast Cancer Therapy by Disturbing Pro-survival Autophagy and Efferocytosis

Triggering immunogenic cell death (ICD) of tumor cells is a promising strategy to enhance the immunogenicity of solid tumors and awaken immune responses. Nevertheless, dying apoptotic tumor cells universally activate phosphatidylserine (PtdSer) scramblases and facilitate the exposure of PtdSer on the cell surface for inducing efferocytosis and the immunosuppressive tumor microenvironment. Here, we identified that the antihelminthic drug niclosamide (NIC), a potent inhibitor of the calcium-activated PtdSer scramblase, could markedly blunt the immunosuppressive PtdSer signal on apoptotic tumor cells and inhibit the efferocytosis of apoptotic tumor cells, showing great potential in overcoming efferocytosis-mediated immunosuppression in vivo. Based on this finding, we hypothesis-driven-prepared a tumor-targeting liposomal nanoparticle (NPs) and a porphyrinic porous coordination network (PCN) for the cooperation of NIC with tumor-targeting chemotherapy and photodynamic therapy (PDT), respectively, both of which are known to be effective in inducing ICD and exposure of PtdSer. In an orthotopic 4T1 mouse breast cancer model, both NIC-based nanoformulations inhibited the macrophage recruitment induced by apoptosis cells and reinvigorated cytotoxic T-cell responses along with enhanced tumor regression. Moreover, we found that intracellular NIC can act as a proton carrier to induce mitochondrial damage and lysosomal alkalization for "pro-death" autophagy induction upon combination therapy with chemotherapy or PDT. Collectively, our study illustrates a general strategy for reversing ICD inducer-mediated exposure of PtdSer and subsequent efferocytosis-mediated immunosuppression, which is expected to be widely used in enhancing the immune-based therapeutic efficiency of cancers.