A Triple‐Synergistic Injectable Hydrogel Elicits Systemic Antitumor Immunity via Mild Photothermal Priming, Radical Storm, and Autophagy Blockade

Abstract

Photothermal therapy (PTT) as a localized cancer treatment modality has gained considerable momentum recently. While conventional PTT relies on photothermal agents (PTAs) to produce abundant heat (above 50°C) via near‐infrared (NIR) laser irradiation for tumor ablation, this high‐temperature approach often inflicts collateral thermal injury on surrounding healthy tissues, which severely constrains the therapeutic feasibility of PTT near vital organs. Therefore, mild‐temperature PTT (below 45°C) is of clinical interest. Herein, we construct an injectable hydrogel (IVH@gel) via the coordination between calcium ions (Ca2+) and sodium alginate to encapsulate the PTA Hu Kaiwen Ink, the free radical initiator 2,2’‐azobis[2‐(2‐imidazolin‐2‐yl)propane]dihydrochloride (VA‐044), and the autophagy inhibitor hydroxychloroquine (HCQ) for realizing synergistic PTT and immunotherapy. Specifically, when irradiated under an NIR laser, the ink in the hydrogel generates heat, which leads to the degradation of VA‐044 to produce free radicals for killing cancer cells; meanwhile, HCQ is released for realizing autophagy‐inhibited mild‐temperature PTT of tumor. More importantly, the IVH@gel‐mediated PTT elicits strong immunogenic cell death (ICD), which activates a potent antitumor immune response, leading to significant tumor inhibition. This work provides a promising method for the development of multifunctional mild‐temperature PTT drugs.