Local delivery of GPC3-CAR T cells in a thermosensitive hydrogel enhances antitumor efficacy in hepatocellular carcinoma.

CAR T cell therapy has demonstrated remarkable antitumor efficacy in hematologic malignancies, but its application in solid tumors remains challenging. This is primarily due to the suppressive tumor microenvironment, which impedes T cell infiltration and reduces their functionality. Compared with standard intravenous administration, localized delivery strategies offer significant promise for CAR T therapy in solid tumors. Nevertheless, most reported approaches rely on complex biomaterials and are mainly applied in immune-privileged tissues. Here, we developed an injectable, thermosensitive chitosan/β-glycerophosphate/gelatin (CS/G/GP) hydrogel for local delivery of GPC3-CAR T cells and the cytokine IL-15 to enhance therapeutic efficacy against solid tumors. This hydrogel not only supported in vitro survival and proliferation of CAR T cells but also limited passive diffusion of IL-15, thereby sustaining GPC3-CAR T cell activity, expansion, and cytotoxicity. In an in vivo NCG mouse model of hepatocellular carcinoma (HCC), hydrogel-mediated local injection markedly enhanced CAR T cell infiltration and antitumor activity within tumor tissues, without apparent systemic toxicity. Overall, our hydrogel platform offers a safe, feasible, and effective strategy for localized CAR T cell therapy, improving treatment efficacy in solid tumors.