Development of a dendritic cell-targeted vaccine strategy using proximity-induced conjugation.

Background: Traditional cancer vaccines that utilize peptides or proteins often exhibit limited efficacy as a result of mutations in cancer antigenic epitopes, also known as antigenic drift, which reduce the ability of traditional vaccines to target tumor antigens and elicit robust immune response. Methods: To address these challenges, we propose an innovative and universal strategy for dendritic cell (DC)-targeted neoepitope delivery via proximity-induced conjugation (PIC). This approach enables the site-specific crosslink of a broad spectrum of neoepitopes tailored to diverse cancer types, thereby increasing both vaccine flexibility and applicability. The PIC method involves the use of recombinant Fc-affinity peptides that are modified with two distinct unnatural amino acids: the photoreactive amino acid p-benzoyl-L-phenylalanine (pBPA) and the bioorthogonal reactive amino acid 4-fluorophenyl carbamate lysine (FPheK). These modified peptides allow for the precise conjugation of neoepitopes through ultraviolet (UV) irradiation or mild incubation, thereby achieving controlled antigen coupling. Results: Through optimization of this strategy, we observed a substantial increase in DCs mediated antigen uptake and processing, leading to enhanced T cell activation, a robust cytotoxic immune response, and significant improvements in antitumor efficacy. Moreover, the DC-targeted vaccine exhibited promising synergistic effects with an immune checkpoint inhibitor (ICI), resulting in a marked reduction in tumor growth and prolonged survival in preclinical models. Conclusion: These findings underscore the potential of the PIC-based DC-targeted vaccine system to augment the immunogenicity, versatility, and therapeutic efficacy of cancer vaccines. This strategy offers a compelling solution to the challenges posed by antigenic drift and mutation, thereby improving clinical outcomes across a broad range of cancers.