A Strategy Based on the Enzyme-Catalyzed Polymerization Reaction of Asp-Phe-Tyr Tripeptide for Cancer Immunotherapy

Immunotherapy has provided a promising strategy for the treatment of cancers. However, even in tumors with high antigen burdens, the systemic inhibition of the antigen presentation still greatly restricts the application of immunotherapy. Here, we construct a tumor protein-engineering system based on the functional tripeptide, Asp-Phe-Tyr (DFY), which can automatically collect and deliver immunogenetic tumor proteins from targeted cells to immune cells. Through a tyrosinase-catalyzed polymerization, the DFY tripeptide selectively accumulates in tyrosinase high-expressed melanoma cells. Then quinone-rich intermediates are covalently linked with tumor-specific proteins by Michael addition and form tumor protein-carried microfibers that could be engulfed by antigen-presenting cells and exhibited tumor antigenic properties for boosting immune effect. In melanoma cells with deficient antigen presentation, this system can successfully enrich and transport tumor antigen-containing proteins to immune cells. Furthermore, in the in vivo study on murine melanoma, the transdermal delivery of the DFY tripeptide suppressed the tumor growth and the postsurgery recurrence. Our findings provide an avenue for the regulation of the immune system on an organism by taking advantage of certain polymerization reactions by virtue of chemical biology.

Automated summary

Immunotherapy presents a promising strategy for cancer treatment, but systemic inhibition of antigen presentation limits its effectiveness. A tumor protein-engineering system based on the DFY tripeptide was developed to collect and deliver tumor proteins to immune cells, enhancing immune response. This system successfully enriched and transported tumor antigen-containing proteins in melanoma cells and suppressed tumor growth and recurrence in murine melanoma study.