Manganese Coordination Micelles That Activate Stimulator of Interferon Genes and Capture In Situ Tumor Antigens for Cancer Metalloimmunotherapy

Cancer immunotherapy holds great promise but is generally limited by insufficient induction of anticancer immune responses. Here, a metal micellar nanovaccine is developed by the self-assembly of manganese (Mn), a stimulator of interferon genes (STING) agonist (ABZI) and naphthalocyanine (ONc) coordinated nanoparticles (ONc-Mn-A) in maleimide-modified Pluronic F127 (malF127) micelles. Owing to synergy between Mn and ABZI, the nanovaccine, termed ONc-Mn-A-malF127, elevates levels of interferon-beta (IFN beta) by 324-and 8-fold in vivo, compared to use of Mn or ABZI alone. As such, the activation of the cyclic guanosine monophosphateadenosine monophosphate synthase (cGAS)-STING pathway induces sufficient dendritic cell (DC) maturation, eventually resulting in the death of CD8+ T cell-sensitive tumors and CD8+ T cell-resistant tumors by simultaneously promoting cytotoxic CD8+ T cells and NK cells, respectively. Furthermore, with ONc used as a Mn chelator and an efficient photosensitizer, photoinduced immunogenic cell death (ICD) of tumor cells releases damage-associated molecular patterns (DAMPs) and neoantigens from dying primary tumor cells upon laser irradiation, which are captured in situ by malF127 in tumor cells and then transported to DCs. After laser treatment, in addition to the photothermal therapy, immune responses characterized by the level of IFN beta are further elevated by another 4-fold. In murine cancer models, ICD-based metalloimmunotherapy using the ONc-Mn-AmalF127 nanovaccine in a single dose by intravenous injection achieved eradication of primary and distant tumors. Taken together, ONc-Mn-A-malF127 offers a nanoplatform to enhance anticancer efficacy by metalloimmunotherapy and photoinduced ICD based immunotherapy with strong abscopal effect.

Automated summary

This study developed a metal micellar nanovaccine that elevates interferon-beta levels by the synergy between Mn and ABZI, resulting in sufficient DC maturation and tumor cell death. Additionally, the use of ONc in laser treatment induces immunogenic cell death and enhances immune responses. Experimental results showed that this nanovaccine achieved strong anticancer efficacy in mouse tumor models.