Supramolecular immunomodulatory hydrogelator potentiates CAR-T therapy with long-lasting endogenous immunity toward solid tumor eradication.

Abstract

The success of chimeric antigen receptor (CAR)-T cell therapy in hematologic malignancies has not been translated to solid tumors, primarily due to inadequate T cell infiltration and an immunosuppressive tumor microenvironment that drives T cell exhaustion. To address these challenges, we developed a tailored immunomodulatory drug-drug conjugate-based hydrogelator for the localized delivery of CAR-T cells targeting solid tumors. This hydrogel forms an in situ scaffold that serves as a sustained-release reservoir, enabling continuous co-delivery of CAR-T cells along with immunomodulatory agents-NLG919 (an IDO-1 inhibitor) and ^DPPA-1 (a PD-L1 antagonistic peptide)-to synergistically remodel the immunosuppressive tumor microenvironment and promote robust tumor recognition and elimination. Notably, this approach significantly enhances CAR-T cell infiltration and persistence, stimulates a potent endogenous tumor-specific immune response, while also establishing long-lasting immunological memory. In murine models of aggressive melanoma, metastatic breast cancer, and postoperative glioma, a single local administration of the hydrogel resulted in significant suppression of tumor growth, rechallenge, metastasis and recurrence. By integrating localized CAR-T cell delivery with in situ immune reprogramming, this system represents a versatile and clinically translatable platform that substantially improves the efficacy of CAR-T cell therapy against solid tumors.