Bladder cancer remains a major clinical challenge due to high recurrence rates and the limitations of current treatments, such as chemotherapy and radiotherapy, which often cause severe side effects. A major obstacle in cancer therapy is the redox adaptability of tumor cells, allowing them to survive oxidative stress.

Nano-Ni0 was synthesized via hydrothermal method and characterized for its structure and catalytic properties. Hydrogen release was analyzed by gas chromatography (GC), while nickel ion release under acidic conditions was quantified by atomic absorption spectroscopy (AAS). Cellular assays evaluated ROS modulation, oxidative damage, autophagy induction, and cell viability in T24 cells. Reductive stress, immunogenic cell death (ICD) markers, and mcrophage polarization was examined.

Nano-Ni0 demonstrated a hydrogen release in acidic conditions and catalyzed H2O2 to generate •OH (chemodynamic therapy (CDT) that caused mitochondrial dysfunction, DNA damage, and autophagy-related cell death. Furthermore, nano-Ni0 treatment triggered ICD, as evidenced by increased CRT exposure on the cancer cell membrane and enhanced extracellular release of HMGB1, signaling immune activation. Additionally, nano-Ni0-treated cancer cells promoted macrophage polarization toward an M1 phenotype, further amplifying anti-tumor immune responses.

This study explores the therapeutic potential of zero-valent nickel nanoparticles (nano-Ni0) by leveraging their dual capability: (1) sustained hydrogen release to induce reductive stress, weakening the cancer cell’s antioxidant defense, and (2) subsequent nickel ion release to trigger CDT-mediated oxidative stress. This disruption of redox homeostasis drives autophagy-related cell death while simultaneously promoting immunogenic cell death (ICD) to enhance anti-cancer immunity. Our findings establish a novel approach to bladder cancer treatment by integrating CDT with immune modulation, paving the way for safer and more effective therapeutic strategies.