ABSTRACT The cyclic GMP‐AMP synthase‐stimulator of interferon gene (cGAS‐STING) signaling pathway plays a crucial role in initiating anti‐tumor immunity. However, its activation is usually suppressed due to cGAS methylation. Therefore, in this work, DSPE‐PEG‐RGD modified molybdenum boride (MoB) MBenes were loaded with SUV39H1 inhibitor chaetocin (MoB/Chae.‐RGD) to alleviate the cGAS methylation for enhanced cancer immunotherapy. The prepared MoB/Chae.‐RGD possessed good catalase‐like capacity and photothermal conversion efficiency. Under 1060 nm laser irradiation, the chaetocin would be released to inhibit cGAS methylation and thus enhance the recognition of cytosolic mtDNA resulting from photothermal‐induced mitochondrial stress, eventually amplifying the cGAS‐STING activation. Meanwhile, the photo induced heating could promote the catalase‐like capacity of MoB/Chae.‐RGD for O 2 generation, whereby both relieving hypoxia and TIME via promoting the polarization of macrophages from the M2 to the M1 phenotype. In addition, the photothermal effect could induce the immunogenic cell death and the exposure of damage‐associated molecular patterns, facilitating the infiltration of T lymphocytes and the generation of a long term immune memory. These combined effects contributed to the mobilization of systemic antitumor immunity and the prevention of pulmonary metastasis. In general, this finding provided novel avenues for immunotherapy of the immune “cold” solid tumors.
Liu et al. (Thu,) studied this question.