Xi Zhang, Qiyue Xuan, Ruishu Mou, Tianming Hu, Ying Xu, Chunying Zhang, S Liu, Yuan Liao, Qingxuan Meng, Qi Liu, Rui Xin, Jiuxin Zhu, Rui Xie
ABSTRACT Photonanocatalytic therapy has considerable potential for remodeling the tumor microenvironment (TME) in liver cancer. In this study, a near‐infrared laser‐activated nanotheranostic platform (denoted as IFMP) is developed to exert a dual phototherapeutic‐enzymatic effect for the coactivation of apoptosis and ferroptosis. Within the acidic TME, IFMP exhibits multi‐enzymatic activities, mimicking peroxidase, catalase, and glutathione oxidase, to convert endogenous H 2 O 2 into •OH and O 2 while depleting glutathione. Upon laser irradiation, the photothermally augmented catalytic activity further enhances photodynamic efficacy by alleviating hypoxia, thereby improving the generation of reactive oxygen species and disrupting redox homeostasis. This integrated effect induces mitochondrial damage and caspase signaling‐pathway activation to trigger apoptosis and facilitates lipid hydroperoxide accumulation and glutathione peroxidase 4 suppression to concurrently drive ferroptosis in cancer cells. Furthermore, the platform is equipped with multimodal imaging capabilities (fluorescence, infrared thermal, and ultrasound), enabling real‐time monitoring of the therapeutic process to realize precise bioimaging‐guided treatment. Consequently, this study highlights the potential of synergistic photonanocatalytic effects for the dual activation of apoptosis and ferroptosis, promoting the development of combinatorial tumor therapies.