Cancer vaccine designed from homologous ferritin-based fusion protein with enhanced DC-T cell crosstalk for durable adaptive immunity against tumors

Abstract

Peptide vaccines based on tumor antigens face the challenges of rapid clearance of peptides, low immunogenicity, and immune suppressive tumor microenvironment. However, the traditional solution mainly uses exogenous substances as adjuvants or carriers to enhance innate immune responses, but excessive inflammation can damage adaptive immunity. In the current study, we propose a straightforward novel nanovaccine strategy by employing homologous human ferritin light chain for minimized innate immunity and dendritic cell (DC) targeting, the cationic KALA peptide for enhanced cellular uptake, and suppressor of cytokine signaling 1 (SOCS1) siRNA for modulating DC activity. Upon fusing with the KALA peptide, this nanovaccine presents as a novel 40-mer cage structure, with highly enriched antigen peptides of proper size (25 nm) for targeted delivery to lymph nodes. The loading of SOCS1 siRNA onto the KALA peptide promoted DC maturation in tumor environment, leading to a 3-fold increase in antigen presentation compared to alum adjuvant. Moreover, it demonstrates remarkable efficacy in suppressing tumor progression and metastasis, together with prolonged survival. In addition, the nanovaccine stimulates up to 40 % memory T cells, thereby achieving sustained protection against tumor re-challenge. This unprecedented nanovaccine platform can ignite fresh interdisciplinary discussions on interactive strategies for future peptide vaccine development.