XOR-mediated tumor-selective nanomaterial therapy: achieving tumor and immune cell dual regulation through intracellular ROS generation.

BACKGROUND: High reactive oxygen species (ROS) concentration displays dual functions, potentially promoting both tumor cell death and driving tumor-associated macrophage (TAM) polarization towards the M1-type to elicit a series of antitumor immune responses, positioning ROS as ideal tumor therapeutic molecules. However, sustained efficacy and precise ROS targeting at tumor sites retains numerous challenges. In this study, we present the synthesis of a nanoplatform, ZIF-8@XOR, comprising Xanthine oxidoreductase (XOR) with high intracellular enzymatic activity for high-level ROS generation and ZIF-8, a versatile zeolite imidazolate framework-8 carrier with high tumor site loading and targeting efficiency. RESULTS: Our results revealed that ZIF-8@XOR targets tumor cells and elicits intracellular ROS both in vitro and in vivo, inducing tumor cell death. Moreover, intracellular ROS elicitation in TAM supports macrophage polarization towards the M1-type. In vivo, tumor-associated antigen pool generation from ROS-induced apoptosis of tumor cells further stimulates increased infiltration and macrophage activation in the tumor microenvironment. This, in turn, leads to increased tumor infiltration of CD8(+) T cells with a cytokine profile, indicating cytotoxic effects and suggesting a successfully induced adaptive anti-tumor response. CONCLUSION: The hereby-presented newly developed nanomaterial could serve as a promising novel tool for gastric cancer immunotherapy.