Biodegradable iridium coordinated nanodrugs potentiate photodynamic therapy and immunotherapy of lung cancer

[Display omitted] Hypoxia, which is a common characteristic of most solid tumors, not only contributes to the immunosuppressive nature of the tumor microenvironment (TME) but also reduces the efficacy of many oxygen-depleting therapies, including photodynamic therapy (PDT). In this study, we developed acidity-responsive biodegradable iridium-coordinated (IPC) nanodrugs consisting of iridium ions, the photosensitizer chlorin e6 (Ce6), and polyvinylpyrrolidone to potentiate the effects of PDT and immunotherapy by modulating the TME. IPC nanodrugs that accumulate at high levels in tumors catalyze excess hydrogen peroxide to produce oxygen while depleting glutathione levels within cancer cells; thus, the released Ce6 is more efficient at producing reactive oxygen species (ROS) in response to laser irradiation. In addition, IPC nanodrugs alleviate tumor hypoxia, induce more immunogenic cell death by amplifying PDT responses, and synergistically inhibit tumor growth by initiating robust antitumor immunity and reversing the immunosuppressive nature of the TME. As a result, IPC nanodrugs exert pronounced combined therapeutic effects in vitro and in vivo, without obvious toxic effects due to acidity-responsive degradation. These iridium-coordinated nanodrugs have the potential to modulate the TME, amplify the effects of PDT, and substantially inhibit tumors, and they are expected to provide novel ideas for combination therapy of hypoxic cancer.