Human Ferritin Platform and Its Optimized Structures to Enhance Anti-Cancer Immunity

Abstract

Although anti-cancer vaccination and immune checkpoint (IC) therapy have emerged as potent cancer treatment modalities, their application remains limited to a subset of patients due to vaccine adjuvant toxicities and IC-blocking antibody-associated systemic immune adverse events. Here, an innovative platform is reported for adjuvant- and antibody-free cancer immunotherapy using human heavy chain ferritin (huHF)-derived optimally designed structures presenting multiple-copies of tumor-specific antigens (TSAs) or IC molecules (ICMs) on their surface. Through structure-guided molecular design, TSA-presenting huHFs for targeting TSAs at dendritic cells (DCs) are constructed with preservation of huHF-intrinsic affinity for transferrin receptors on DCs, and multi-copies of an ICM are also presented on huHF for blocking a cognate regulatory IC. The adjuvant-free co-administration of TSA- and ICM-presenting huHFs effectively elicits TSA-specific CD8+ T cell activation, strikingly suppresses both tumor growth and interleukin 17+ CD4+ T cell responses, and generates long-lasting protective immunity, indicating that this novel approach offers a promising breakthrough in cancer immunotherapy.