In situ TLR7 activation with biocompatible injectable hydrogel for synergistic chemo-immunotherapy

Abstract

Colorectal peritoneal carcinomatosis (CRPC) is a manifestation of colorectal cancer characterized by aggressive tumor growth. Clinically, patients are typically treated with cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. However, this strategy is only suitable for a subset of patients and may result in severe side effects. Therefore, we explored a novel approach using green-engineered materials that we developed an injectable hydrogel (CPE) based on polyphenol-borate ester bonds by functionalizing chitosan. These biopolymer composites exhibit excellent biocompatibility, mitigating drug-related toxicities. Our hydrogel delivery system concurrently administers cabazitaxel and imiquimod (R837) for localized chemotherapy and immunotherapy. Cabazitaxel-mediated chemotherapy induces immunogenic cell death (ICD) of tumor cells, releasing tumor-associated antigens (TAAs), that promote dendritic cell maturation and cytotoxic T lymphocyte (CTL) infiltration. The in situ release of the TLR7 agonist R837 further stimulates the immune system, inducing an effective and sustained antitumor immune response tailored to CRPC. In summary, by establishing an in situ drug reservoir, we effectively inhibited tumor invasion and progression and induced a durable immune response, offering a new perspective on localized immunotherapy for the clinical treatment of CRPC.