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

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 (H₂ 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 H₂ 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 H₂ S-modulated PTT with adaptive immune response is thus recommended as an advanced strategy to cancer therapeutics.