A Locally Retentive HfO 2 –STING Nano‐Radiosensitizer Hydrogel for Enhanced Radioimmunotherapy in Esophageal Cancer

ABSTRACT Esophageal squamous cell carcinoma (ESCC) remains associated with frequent local recurrence and distant metastasis despite advances in radiochemotherapy and immunotherapy, highlighting the need for therapeutic strategies that improve both local tumor control and systemic antitumor immune responses. Herein, we developed an Hf‐based radio‐immunotherapeutic platform composed of HfO 2 @PDA/cGAMP‐PEG nanoparticles (HPG NPs) embedded in a catechol‐modified methacrylated chitosan photocurable adhesive hydrogel (HPGC). This platform was designed as a locally retentive and sustained‐release matrix for ESCC treatment. HPG NPs exhibited uniform morphology, favorable colloidal stability, and sustained cGAMP release, whereas HPGC showed injectability, rapid photocrosslinking, wet‐tissue adhesion, controlled degradation, and cytocompatibility. In vitro, HPG NPs combined with radiotherapy suppressed ESCC cell proliferation and migration and were associated with enhanced immunogenic cell death (ICD)‐related signals and increased dendritic‐cell maturation. In immunocompetent mice bearing mEC25 tumors, HPGC + RT improved local tumor control and survival compared with HPG NPs + RT under the tested conditions, accompanied by increased intratumoral CD8 + T‐cell infiltration, reduced myeloid‐derived suppressor cells and regulatory T cells, and elevated IFN‐γ, TNF‐α, and IL‐12p70 levels. Moreover, HPGC + RT was associated with increased CD8 + effector memory T‐cell responses and reduced secondary tumor growth and lung metastasis, without obvious systemic toxicity under the tested dose and observation period. These findings support HPGC as a locally retentive adhesive hydrogel platform for integrating high‐ Z radiosensitization, STING‐associated immune activation, local tumor control, and systemic antitumor immune responses in ESCC.