Tumor Microenvironment‐Responsive Hydrogen‐Generating Zn‐Doped ReZIF‐8 Nanoplatform for Enhanced Tumor Suppression

Abstract Hydrogen‐based tumor therapy demonstrates therapeutic potential, while the efficacy remains limited by insufficient intracellular hydrogen generation, poorly controlled release kinetics, and inadequate immune response potentiation. To address these limitations, a partially reduced zinc‐doped zeolitic imidazolate framework‐8 (ReZIF‐8) is developed, functioning as a dual‐functional nanoplatform for both intracellular hydrogen generation and controlled Zn(II) ions (Zn 2+ ) overload. The cationic surface charge of ReZIF‐8 enhances cellular internalization, while its pH‐responsive properties facilitate controlled intracellular hydrogen gas (H 2 ) release. The accumulated H 2 and Zn 2+ overload act synergistically to disrupt redox homeostasis in tumor cells, inducing reactive oxygen species (ROS)‐dependent immunogenic cell death (ICD). This ICD activation robustly stimulates innate immune responses and enhances antigen cross‐presentation. Intratumoral administration of ReZIF‐8 in a B16F10 melanoma mouse model elicits potent antitumor efficacy via intracellular H 2 ‐triggered terminal differentiation and cell cycle arrest. The therapeutic effect is further enhanced in combination with αPD‐1 immune checkpoint blockade, resulting in extended survival and significant suppression of metastatic progression, highlighting its translational potential. The ReZIF‐8‐mediated H 2 ‐generating nanoplatform reprograms intratumoral redox balance to simultaneously induce ICD, amplify antitumor immunity, and drive terminal differentiation. This triple‐pronged mechanism leverages synergistic modulation to achieve comprehensive tumor control.