Rational Design of an Immunomodulation Gelator Enabling an Injectable Hydrogel for Amplified Tumor Immunotherapy

Abstract

Arginase 1 (ARG1) inactivates T cells by degrading L-arginine, severely reducing the immunotherapeutic efficacy. Effectively blocking the ARG1 pathway remains a challenge. L-norvaline is a very cheap and negligible side effect inhibitor of ARG1, but its blockage efficacy for ARG1 is impeded by its high half-maximal-inhibitory concentration (IC50) requiring high drug loading content of L-norvaline in carriers, as well as its high water solubility leading to bursting and uncontrolled release. Herein we reported a novel injectable hydrogel strategy via an L-norvaline-based immunomodulation gelator that could effectively block ARG1 pathway. The designed gelator was a diblock copolymer containing L-norvaline-based polypeptide block, which could construct a thermally responsive injectable hydrogel by its self-gelation in tumor micro-environment. The hydrogel not only ensures high drug loading of L-norvaline, but also ensures controlled release of L-norvaline through responsive peptide bond cleavage, thereby solving the problems encountered by L-norvaline. The injectable hydrogel in combination with doxorubicin hydrochloride demonstrated an excellent immunotherapy for removal of primary tumors, suppression of abscopal tumors and inhibition of pulmonary metastasis by combing the blockage of ARG1 pathway and the immunogenic cell death. Our immunomodulation gelator strategy provides a robust injectable hydrogel platform to efficiently reverse ARG1 immunosuppressive environment for amplified immunotherapy.