Tumor‐Associated Myeloid Cells Selective Delivery of a Therapeutic Tumor Nano‐Vaccine for Overcoming Immune Barriers for Effective and Long‐Term Cancer Immunotherapy

Abstract Therapeutic cancer vaccines have the potential to induce regression of established tumors, eradicate microscopic residual lesions, and prevent metastasis and recurrence, but their efficacy is limited by the low antigenicity of soluble antigens and the immunosuppressive tumor‐associated macrophages (TAMs) that promote tumor growth. In this study, a novel strategy is reported for overcoming these defenses: a dual‐targeting nano‐vaccine (NV) based on hepatitis B core antigen (HBcAg) derived virus‐like particles (VLPs), N‐M2T‐gp100 HBc NV, equipped with both SIGNR + dendritic cells (DCs)/TAMs‐targeting ability and high‐density display of tumor‐associated antigen (TAA). N‐M2T‐gp100 HBc NVs‐based immunotherapy has demonstrated an optimal interaction between tumor‐associated antigens (TAAs) and the immune composition of the tumor microenvironment. In a melanoma model, N‐M2T‐gp100 HBc VLPs significantly reducing in situ and abscopal tumor growth, and provide long‐term immune protection. This remarkable anti‐tumor effect is achieved by efficiently boosting of T cells and repolarizing of M2‐like TAMs. This work opens exciting avenues for the development of personalized tumor vaccines targeting not just melanoma but potentially a broad range of cancer types based on functionalized VLPs.