ABSTRACT: Colorectal cancer treatment remains difficult, with traditional approaches restricted by indications, toxicity, and resistance. In this study, we present a tumor microenvironment-responsive nanoplatform, Cu2O@AuMn@HA, that induces ferroptosis through photothermally enhanced dual enzyme-like activities, thereby improving the immunotherapy outcome of CRC. Leveraging hyaluronic acid, the platform selectively targets CD44-overexpressing cells and undergoes conversion to CuxS in response to the elevated H2S levels within tumors, achieving in situ photothermal therapy (PTT) while consuming endogenous hydrogen sulfide (H2S). The nanoplatform exhibits both peroxidase-like (POD-like) and glutathione oxidase-like (GSHOx-like) catalytic activities, promoting reactive oxygen species (ROS) generation while depleting glutathione, thereby disrupting redox homeostasis and driving ferroptosis. Simultaneously, the photothermal effect accelerates these catalytic reactions, further enhancing therapeutic efficacy. Ferroptosis, combined with photothermal stress, provokes immunogenic cell death (ICD), which facilitates immune cells infiltration, and alleviates the immunosuppressive tumor microenvironment. Moreover, the incorporation of Au and Mn endows the platform with triple-modal imaging capabilities -fluorescence imaging, computed tomography (CT), and magnetic resonance imaging (MRI)- enabling precise localization and real-time monitoring at both the cellular and animal levels. In vitro and in vivo experiments demonstrate near-complete tumor eradication in CRC models via a photothermal-nanocatalytic-immune triple-synergistic mechanism, with favorable safety profiles. This study introduces a multifunctional, scalable, precision-based diagnostic and therapeutic strategy for CRC, providing novel insights for future clinical translation.
