Hydrogen enhanced photothermal therapy for redox-regulated tumor apoptosis and immune reprogramming

Photothermal-catalysis enables controlled hydrogen release and redox modulation, with applications in biomedical therapy. Despite growing interest in hydrogen therapy, its effects on immune cells within the tumor microenvironment (TME) remain insufficiently elucidated, specifically regarding selective redox modulation and immune activation. Herein, we present H atoms stabilize the rhodium palladium bimetallene (RhPd-H) nanosheets as a hydrogen-loaded photothermal-catalytic platform with NIR-triggered release for targeted redox modulation in TME. Upon NIR irradiation, RhPd-H serves as a dual-source of hydrogen and localized heat, inducing reactive oxygen species (ROS) bursts that selectively disrupt tumor redox homeostasis, leading to apoptosis of tumor cells. Synergistically, hydrogen scavenges ROS in immune cells, protecting them from oxidative stress and further promoting dendritic cell maturation, T-cell activation, and macrophage polarizaion for exerting anti-tumor effects. Experimental data reveals the synergy of hydrogen-photothermal therapy in ablating tumors and reprograming the immunosuppressive TME, as evidenced by enhanced antigen presentation, amplified T-cell infiltration and systemic anti-tumor memory responses. Particularly, we report the novel finding that hydrogen performs both protective and activating effects on immune cells, which to our knowledge has not been previously documented, revealing a veil of mystery of hydrogen therapy. By integrating hydrogen-mediated redox editing and immunomodulation, this work establishes a paradigm-shifting strategy for precise tumor therapy. STATEMENT OF SIGNIFICANCE: This work unveils a paradigm-shifting duality of hydrogen (H₂) within the tumor microenvironment: simultaneously acting as a pro-oxidative inducer of reactive oxygen species (ROS) bursts in tumor cells while serving as a protective antioxidant and immunomodulator in immune cells. Under NIR irradiation, H₂ released from hydrogen-stabilized rhodium-palladium bimetallene (RhPd-H) nanosheets synergizes with photothermal energy to disrupt redox homeostasis and trigger selective apoptosis in tumors. Concurrently, in immune cells, H₂ scavenges photothermal-induced ROS-shielding them from oxidative damage while activating dendritic cell maturation, cytotoxic T-cell infiltration, and macrophage polarization toward antitumor phenotypes. This cell-contextual redox switching not only ablates tumors directly but also reprograms the immunosuppressive microenvironment, revealing an unprecedented biological mechanism for hydrogen therapy and establishing differential redox editing as a transformative strategy for precision cancer treatment.