Activating Innate Immunity by a STING Signal Amplifier for Local and Systemic Immunotherapy

The number of patients who benefit from acquired immunotherapy is limited. Stimulator of interferon genes (STING) signal activation is a significant component to enhance innate immunity, which has been used to realize broad-spectrum immunotherapy. Here, M@P@HA nanoparticles, as a STING signal amplifier, are constructed to enhance innate immunotherapy. Briefly, when M@P@HA was targeted into tumor cells, the nanoparticles decomposed with Mn2+ and activated the release of protoporphyrin (PpIX). Under light irradiation, the generated reactive oxygen species disrupt the cellular redox homeostasis to lead cytoplasm leakage of damaged mitochondrial double-stranded (ds) DNA, which is the initiator of the STING signal. Simultaneously, Mn2+ as the immunoregulator could significantly increase the activity of related protein of a STING signal, such as cyclic GMP-AMP synthase (cGAS) and STING, to further amplify the STING signal of tumor cells. Subsequently, the STING signal of tumor-associated macrophages (TAM) is also activated by capturing dsDNA and Mn2+ that escaped from tumor cells, so as to enhance innate immunity. It is found that, by amplifying the STING signal of tumor tissue, M@P@HA could not only activate innate immunity but also cascade to activate CD8(+) T cell infiltration even in a tumor with low immunogenicity.

Automated summary

In this study, M@P@HA nanoparticles were used as a STING signal amplifier to enhance innate immunotherapy in tumors. The nanoparticles released reactive oxygen species under light irradiation, disrupting cellular redox homeostasis and initiating the STING signal through damaged mitochondrial dsDNA. The immunoregulator Mn2+ increased the activity of cGAS and STING, further amplifying the STING signal in tumor cells. Additionally, the STING signal of TAMs was activated by capturing dsDNA and Mn2+ that escaped from tumor cells, enhancing innate immunity.