Oxygen Self-Sufficient Ir–Mn ^II/III Coordination-Assembled Nanoparticles Evoke Apoptosis and Ferroptosis for Boosting Hypoxic Melanoma Photoimmunotherapy

Photoimmunotherapy, recognized as the fifth modality of cancer treatment, integrates phototherapy with immunotherapy to enhance therapeutic outcomes. However, its immunomodulatory efficacy is often constrained by the tumor hypoxic microenvironment and single-immunostimulatory mechanisms. To address these challenges, we developed pH-light cascade-responsive nanoparticles (<b>Ir-Mn</b>^{<b>II/III</b>}<b>NPs</b>) via coordination-driven assembly of a two-photon photosensitizer (<b>Ir-OH</b>) and immunoadjuvant Mn ions. <b>Ir-Mn</b>^{<b>II/III</b>}<b>NPs</b> dissociate in the acidic lysosomal environment and activate upon irradiation, alleviating hypoxia <i>via in situ</i> oxygen generation and downregulating hypoxia-inducible factor 1α (HIF-1α) and programmed cell death ligand 1 (PD-L1) to reverse the immunosuppressive microenvironment. Abundant reactive oxygen species (ROS) produced by photodynamic and Fenton-like reactions induce lysosomal membrane permeabilization, facilitating the escape of <b>Ir-OH</b> into mitochondria. This process activates both ferroptosis and mitochondrial apoptosis to trigger immunogenic cell death (ICD). Moreover, mitochondrial damage-induced mtDNA release synergizes with the stimulator of interferon genes (STING) agonist Mn²⁺ to activate the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) -STING pathway, amplifying antitumor immunity. In a murine orthotopic melanoma model, <b>Ir-Mn</b>^{<b>II/III</b>}<b>NPs</b> effectively reverses the immunosuppressive tumor microenvironment and achieves excellent photoimmunotherapeutic efficacy. This work presents a strategy for pH-light cascade-responsive and immune microenvironment remodeling via photoimmunotherapy, offering a promising direction for developing cancer treatments.