Promoting the Recruitment, Engagement, and Reinvigoration of Effector T Cells via an Injectable Hydrogel with a Supramolecular Binding Capability for Cancer Immunotherapy

Abstract T cells play a basic and key role in immunotherapy against solid tumors, and efficiently recruiting them into neoplastic foci and sustaining long‐term effector function are consistent goals that remain a critical challenge. Here, an injectable alginate‐based hydrogel with abundant β‐cyclodextrin (ALG‐βCD) sites is developed and intratumorally injected to recruit CCR9⁺CD8⁺ T cells (a subset of T cells with robust antitumor activity) via the trapped chemokine CCL25. In the meantime, an intravenously injected adamantane‐decorated anti‐PD1 antibody (Ad‐aPD1) would hitchhike on recruited CCR9⁺CD8⁺ T cells to achieve the improved intratumoral accumulation of Ad‐aPD1. Moreover, the Ad‐PD1 and Ad‐PDL1 antibodies are immobilized in the ALG‐βCD hydrogel through supramolecular host–guest interactions of Ad and βCD, which facilitate engagement between CD8⁺ T cells and tumor cells and reinvigorate CD8⁺ T cells to avoid exhaustion. Based on this treatment strategy, T cell‐mediated anticancer activity is promoted at multiple levels, eventually achieving superior antitumor efficacy in both orthotopic and postsurgical B16‐F10 tumor models.