Engineering a Hydrogen‐Sulfide‐Based Nanomodulator to Normalize Hyperactive Photothermal Immunogenicity for Combination Cancer Therapy

Abstract Photothermal therapy (PTT), one of the most‐potent cancer therapeutic strategies known, is highlighted with excessive inflammatory response, while ablating cancer with immunogenic death. This hyperactive immune response may override PTT‐triggered immunogenicity, exacerbate skin empyrosis, and incur permanent tissue injury and high‐profile tumor regeneration. Therefore, an anticancer balance between pathological and protective immune response is urgently needed for an advanced photothermal therapeutic tactic. Herein, a gas‐modulated photothermal immunogenicity strategy is proposed by integrating an amphiphilic‐conjugated polymer with a polysulfide‐based hydrogen sulfide (H 2 S) donor (2,2′‐dipyridyl tetrasulfide@CP‐PEG) (where CP = conjugated polymer and PEG = poly(ethylene glycol)). The CP is endowed with NIR‐II fluorescence capacity and favorable photothermal effect, tracing the tumor for precise therapeutics. The polysulfide donor can release H 2 S triggered by intracellular glutathione, which elicits mitochondrial dysfunction and robust anti‐inflammation effect. Ultimately, this gas‐modulated PTT strategy inhibits tumor growth remarkably and limits the magnitude of PTT‐induced proinflammatory tumor necrosis factor‐alpha (TNF‐α), interleukin‐6 (IL‐6), and interleukin‐1beta (IL‐1β) cytokines. Moreover, the regulated inflammation accelerates PTT‐induced wound healing. A H 2 S‐modulated PTT with adaptive immune response is thus recommended as an advanced strategy to cancer therapeutics.