Targeting the Cancer-Retina Antigen PDE6G with mRNA-LNP Vaccine Elicits Potent Anti-Tumor Immunity Against Breast Cancer
The development of effective mRNA vaccines for breast cancer has been constrained by the lack of highly immunogenic and tumor-specific antigens. Here, we identify PDE6G, an immune-privileged retina-enriched antigen aberrantly overexpressed in breast tumors, and develop a PDE6G mRNA-LNP vaccine. Vaccination elicited robust CD8+ T cell responses, promoted clonal expansion of effector and IFN-competent T cell subsets, and suppressed tumor growth without detectable toxicity. Single-cell RNA  sequencing (scRNA-seq) revealed that vaccination of PDE6G mRNA-LNP reshapes the tumor immune microenvironment (TIME) by expanding antigen-presenting Cd74+ tumor-associated macrophages (TAMs) while reducing immunosuppressive Maf+ macrophages, and enhancing crosstalk between macrophages and CD8+ T cells. Moreover, combining PDE6G mRNA-LNP with PD-1 blockade further improved anti-tumor efficacy. These findings establish cancer-retina antigens as promising vaccine targets and demonstrate that PDE6G mRNA-LNP coordinates adaptive immunity and tumor microenvironment remodeling, providing a safe and potent strategy for breast cancer immunotherapy. Overall design: PDE6G-expressing tumor models (experimental group) were immunized with PDE6G mRNA-LNP vaccine