Injectable shear-thinning polylysine hydrogels for localized immunotherapy of gastric cancer through repolarization of tumor-associated macrophages

Abstract

Immunotherapy has emerged as one of the most promising treatments for cancer in recent years. However, it works only for a small proportion of patients, which can in part be attributed to the immunosuppressive tumor microenvironment (TME). Tumor associated macrophages (TAMs) are the critical components of tumors and play an important role in the development of the immunosuppressive TME. The transition of TAMs from the pro-tumor (M2) phenotype to anti-tumor (M1) phenotype is crucial for the immunotherapy of gastric cancer. Herein, we developed a shear-thinning, injectable hydrogel co-loaded with polyphyllin II (PP2) and resiquimod (R848) (PR-Gel) for potentiating localized immunotherapy of gastric cancer through the repolarization of TAMs. In this work, we evaluate the effects of PR-Gel on TAM repolarization and explored its therapeutic effect for localized immunotherapy. The hydrogels were synthesized through the Schiff base reactions between aldehyde-functionalized polyethylene glycol and the amino group of polylysine. A M2-to-M1 repolarization of TAMs and increased production of TNF-α and IL-6 were observed after treatment with PR-Gel in vitro. The anti-tumor efficacy of PR-Gel in a subcutaneous xenograft model of gastric cancer showed that the hydrogels possess good tumor growth suppression properties after a single injection. Furthermore, an increased iNOS/CD206 ratio in TAMs and enhanced CD8+ T cell infiltration were also observed within the TME after the treatment with PR-Gel. Hence, the biocompatible, shear-thinning, injectable hydrogels are a promising noninvasive drug-delivery platform for the regulation of the immunosuppressive TME and have great potential in localized immunotherapy against gastric cancer.