Abstract
Immune adjuvants play a critical role in cancer vaccines and emerging therapies. However, conventional adjuvants may fail to effectively stimulate cytotoxic T lymphocyte (CTL)-mediated immune responses. Nanozyme-based adjuvants, particularly manganese-based nanozymes, demonstrate significant potential by integrating enzymatic activity with immune modulation. Herein, we developed a dual-enzyme-like nanozyme adjuvant (Mn(3)O(4)&MLT@PDA-AS1411, MMPA) through the integration of Mn(3)O(4) nanozyme and melatonin (MLT) using polydopamine, which alleviates tumor hypoxia to enhance photothermally augmented ferroptosis-immune synergistic therapy. The ferroptosis is cooperatively enhanced by Mn(3)O(4) nanozyme-mediated reactive oxygen species generation and glutathione depletion, synergizing with MLT-induced HIF-1α suppression. Concurrently, HIF-1α inhibition and ferroptosis activation cooperate to suppress HSP70 expression, thereby amplifying the mild photothermal therapy and synergistically inducing immunogenic cell death. Furthermore, the degradation product of MMPA, Mn(2+), activates the cGAS-STING pathway and promotes dendritic cell maturation and CTL infiltration. In vivo studies demonstrate that this strategy effectively alleviates tumor hypoxia, resulting in the complete suppression of distant tumors in a metastatic model. This approach also first explores the promotion of ferroptosis and immune activation of MLT, providing an innovative strategy for multi-mechanism synergistic treatment.