In situ non-canonical activation and sensitization of cGAS-STING pathway with manganese telluride nanosheets.

Abstract

Immune checkpoint blockade (ICB) has achieved encouraging outcome in various malignant tumors. However, the low immunogenicity and insufficient infiltration of T cells within tumors severely limit the curative effects. Herein, we reported synthesis and experimental evaluation of H₂O₂-responsive MnTe₂ nanosheets (NSs) for improving anti-tumor immune responses. Within the tumor microenvironment characterized by high level of H₂O₂, the MnTe₂ NSs were degraded to release Mn²⁺ and TeO₄^2- which subsequently induced cellular endoplasmic reticulum (ER) stress and non-canonically activated the cGAS-STING pathway. Moreover, the cellular Mn²⁺ ions enhanced the sensitivity of cGAS-STING pathway and the maturation of dendritic cells (DCs) concurrently. Ultimately, the MnTe₂ NSs exhibited favorable in vivo anti-tumor immune effects, especially in combination with PD-L1 checkpoint inhibitors. These findings provided compelling evidence for exploration and utilization of nanomedicine to leverage innate immune system for better tumor immunotherapy.