Hypoxia Reversion and STING Pathway Activation through Large Mesoporous Nanozyme for Near-Infrared-II Light Amplified Tumor Polymetallic-Immunotherapy.

cGAS/STING pathway, which is highly related to tumor hypoxia, is considered as a potential target for remodeling the immunosuppressive microenvironment of solid tumors. Metal ions, such as Mn, activate the cGAS/STING pathway, but their efficacy in cancer therapy is limited by insufficient effect on immunogenic tumor cell death of a single ion. Here, we evaluate the association between tumor hypoxia and cGAS/STING inhibition and report a polymetallic-immunotherapy strategy based on large mesoporous trimetal-based nanozyme (AuPdRh) coordinated with Mn (Mn@AuPdRh) to activate cGAS/STING signaling for robust adaptive antitumor immunity. Specifically, the inherent CAT-like activity of this polymetallic Mn@AuPdRh nanozyme decomposes the endogenous HO into O to relieve tumor hypoxia induced suppression of cGAS/STING signaling. Moreover, the Mn@AuPdRh nanozyme displays a potent near-infrared-II photothermal effect and strong POD-mimic activity; and the generated hyperthermia and OH radicals synergistically trigger immunogenic cell death in tumors, releasing abundant dsDNA, while the delivered Mn augments the sensitivity of cGAS to dsDNA and activates the cGAS-STING pathway, thereby triggering downstream immunostimulatory signals to kill primary and distant metastatic tumors. Our study demonstrates the potential of metal-based nanozyme for STING-mediated tumor polymetallic-immunotherapy and may inspire the development of more effective strategies for cancer immunotherapy.