Electrostatic engineering of FcγR-targeted rF9R protein enhances cancer vaccine efficacy and tumor regression

Effective cancer vaccines face significant challenges in achieving potent and sustained immune responses while maintaining safety and simplifying formulation. Current peptide-based vaccines often require complex delivery systems to overcome their inherent instability and poor immunogenicity. This study addresses the critical need for advanced delivery platforms that can efficiently present tumor antigens to antigen-presenting cells (APCs). By leveraging the natural Fcγ receptor (FcγR) targeting ability of FLIPr (formyl peptide receptor-like 1 inhibitory protein), researchers aimed to develop a novel system to enhance vaccine efficacy and overcome limitations of traditional approaches.

Researchers engineered a recombinant FLIPr variant, named rF9R, by adding nine arginine residues to its C-terminus to facilitate electrostatic binding with anionic vaccine components. To optimize this interaction, tumor antigen epitopes were further modified with five aspartic acid residues. The platform's ability to form stable complexes with various components, including peptides, CpG oligodeoxynucleotides, and protein antigens, was rigorously evaluated in vitro. Subsequently, the efficacy of the rF9R/rE7m complex was tested in tumor models to assess CD8+ T-cell activation and its impact on tumor regression.

The engineered rF9R protein successfully bound a diverse range of peptides and antigens, forming stable complexes that significantly enhanced antigen delivery to target cells and subsequently boosted immune activation. In vivo experiments demonstrated that the rF9R/rE7m complex, both as a standalone treatment and when combined with CpG oligodeoxynucleotides, elicited robust CD8+ T-cell responses. This potent immune activation was directly correlated with significant tumor regression across the studied models. The platform's dual functionality as an efficient carrier and a potent immunostimulatory component was a key finding.

The rF9R platform functions as both an efficient carrier and a potent immunostimulatory component, leading to significant tumor regression in vivo.