Nanocarrier-based activation of necroptotic cell death potentiates cancer immunotherapy

Even though immunological checkpoint inhibitors have demonstrated a potent anti-tumor effect in clinical practice, the low immunogenicity of the majority of tumors still results in a lower response rate and a higher resistance to mono-immunotherapy. Recent studies revealed that immunogenic cell death (ICD) augments T cell responses against some cancers, thus indicating that this combination therapy may further improve the anti-tumor immunity produced by anti-PD-1/PD-L1. Herein a robust synergetic strategy is reported to integrate the activation of necroptotic cell death and the subsequent using of immune checkpoint inhibitors. Liposomes have good biocompatibility and are widely used as drug carriers. Using liposomes as TNF-alpha-loaded nanoplatforms achieves in vivo tumor targeting and long-term retention in the tumor microenvironment. Tumor cells treated with TNF-alpha-loaded liposomes exhibited the hallmarks of ICD including the release of high mobility group box 1 (HMGB1) and lactate dehydrogenase (LDH). Additionally, the tumor cell necrosis caused by TNF-alpha induces the in situ release of tumor-specific antigens, thus increasing the dendritic cell (DC) activation and T cell infiltration when combined with the checkpoint blockade therapy. Collectively, significant tumor reduction is accomplishable by this synergetic strategy, in which TNF-alpha-loaded liposomes convert the tumor cell into an endogenous vaccine and improve the anti-tumor immunity of anti-PD-1/PD-L1.