Leveraging SARS-CoV-2-induced pre-existing humoral and cellular immunity for tumor elimination.

Tumor immunotherapy has demonstrated clinical success in some patients, but its efficacy in most solid tumors is hampered by poor infiltration of tumor-specific cytotoxic T lymphocytes (CTLs). Activating virus-specific bystander T cells via loading viral epitopes onto tumor-associated MHC class I molecules can induce antitumor immunity, but this approach is restricted by MHC polymorphism and individual infection histories. Here, we developed a hepatocellular carcinoma-targeted adeno-associated virus system that directs full-length membrane-anchored expression of the SARS-CoV-2 receptor-binding domain on tumor cells. This design bypasses MHC class I epitope pre-screening by activating pre-existing SARS-CoV-2-specific CTLs to exert potent cytotoxicity, and simultaneously engaging humoral immunity to induce antibody-dependent cell-mediated cytotoxicity. In a murine hepatocellular carcinoma model, our treatment markedly reduced tumor burden. It also enhanced infiltration of pre-existing bystander immune cells, accompanied by increased intratumoral IFN-γ+ CD8+ T cells and perforin-1+ NK cells. These findings demonstrate that leveraging pre-existing SARS-CoV-2 immunity to convert immunologically "cold" tumors into immune-recognizable targets, providing a promising translational strategy for refractory malignancies.