Mitoxyperiosis‐Driven Immunotherapy Enabled by Photothermal Ru‐Doped MXene/MoS 2 Nanozymes for Systemic Immunity Against Oral Squamous Cell Carcinoma

ABSTRACT The immune‐privileged oral squamous cell carcinoma (OSCC) microenvironment and low vaccine immunogenicity hinder lymphocyte recruitment, driving recurrence and lymph node metastasis and highlighting the need for better therapies. Herein, we report a 1T/2H‐enriched Ru‐doped MXene/MoS 2 (RMT) heterostructure engineered for synergistic photothermal‐enhanced nanozyme catalysis and mitoxyperiosis‐based therapy to boost immunotherapeutic efficacy. Ru incorporation and MoS 2 phase engineering generate abundant active sites and optimize electronic structures, enabling enhanced catalytic activity. Under TME conditions (acidic pH, elevated glutathione, and H 2 O 2 ), RMT exhibits catalase‐ and peroxidase‐like activities, decomposing H 2 O 2 into O 2 and hydroxyl radicals (•OH), thereby amplifying oxidative stress and alleviating hypoxia. The strong near‐infrared (NIR) absorption of MXene enables efficient photothermal conversion, further accelerating catalytic reactions. The generated reactive oxygen species (ROS) induce mitochondrial dysfunction and membrane disruption, triggering mitoxyperiosis. Notably, rapid thermal suppression of mitochondrial apoptosis combined with sustained mitophagy induction enables precise regulation of mitochondrial activity. In vivo, RMT achieves deep tumor penetration and extensive tumor ablation, resulting in significant regression. Moreover, this combined therapy induces immunogenic cell death (ICD), promotes dendritic cell maturation, and activates systemic antitumor immune responses. Overall, RMT provides a versatile platform for integrating nanozyme catalysis, photothermal therapy, and mitochondrial targeting to overcome immunosuppressive OSCC.