An Injectable Hydrogel Co‐Delivering Propranolol and Imiquimod to Synergistically Enhance Immunogenic Cell Death after Melanoma Resection

Abstract Melanoma remains one of the most aggressive skin cancers with high recurrence rates following surgical resection. To overcome the challenges of residual tumor cells and postoperative immune resistance, an injectable hydrogel is developed that co‐delivers propranolol (Pro) and imiquimod (IMQ). The rationale is to achieve a synergistic therapeutic effect by enhancing immunogenic cell death (ICD) and strengthening antitumor immunity. The hydrogel is synthesized via boronate ester crosslinking between HA‐EGCG and CMCS‐PBA and demonstrates excellent injectability, self‐healing, biodegradability, and tissue adhesion. In vitro, Pro potentiated IMQ‐induced reactive oxygen species (ROS) production, enhancing ICD markers such as calreticulin exposure (CRT), high mobility group box 1 (HMGB1), and adenosine triphosphate (ATP) release, thereby promoting dendritic cell maturation and T cell activation. In vivo, Pro/IMQ@ Hydrogel (PIH) effectively inhibited tumor recurrence in an incomplete melanoma resection model, significantly reducing tumor volume and inducing apoptosis without systemic toxicity. Immunohistochemical analyses revealed increased CD8⁺ and CD4⁺ T cell infiltration, elevated inflammatory cytokine levels, and enhanced memory T cell responses. This work highlights the potential of PIH as a potent localized chemo‐immunotherapy platform for melanoma by converting “cold” tumors into “hot” immunogenic lesions.