This article presents a novel lymph-targeted high-density lipoprotein-mimetic nanovaccine for personalized cancer immunotherapy. The vaccine is designed to deliver multiple tumor-associated antigens along with an immune adjuvant, R837, to lymph nodes, where it can effectively stimulate cytotoxic T lymphocyte (CTL) responses. The nanovaccine is based on lipid nanoparticles (LNPs) that are coated with cancer cell membranes containing tumor antigens and modified with an ApoA1-mimetic peptide to enhance lymphatic targeting and dendritic cell (DC) uptake. The study demonstrates that the optimized nanovaccine significantly enhances antigen delivery to lymph nodes, promotes DC activation, and elicits strong CTL responses, leading to suppression of tumor growth and improved therapeutic efficacy of immune checkpoint inhibitors, particularly in high-stemness melanoma models. The nanovaccine is shown to effectively target lymphatic vessels through the SR-BI receptor, enhancing its accumulation in lymph nodes and improving immune surveillance. The study also highlights the importance of nanoparticle properties such as core composition, particle size, surface charge, and surface modification in determining lymphatic targeting and DC uptake efficiency. The vaccine is safe and well-tolerated, with no observed liver or kidney toxicity, and has the potential for further clinical translation. The findings suggest that this HDL-mimetic nanovaccine represents a promising approach for personalized cancer immunotherapy.This article presents a novel lymph-targeted high-density lipoprotein-mimetic nanovaccine for personalized cancer immunotherapy. The vaccine is designed to deliver multiple tumor-associated antigens along with an immune adjuvant, R837, to lymph nodes, where it can effectively stimulate cytotoxic T lymphocyte (CTL) responses. The nanovaccine is based on lipid nanoparticles (LNPs) that are coated with cancer cell membranes containing tumor antigens and modified with an ApoA1-mimetic peptide to enhance lymphatic targeting and dendritic cell (DC) uptake. The study demonstrates that the optimized nanovaccine significantly enhances antigen delivery to lymph nodes, promotes DC activation, and elicits strong CTL responses, leading to suppression of tumor growth and improved therapeutic efficacy of immune checkpoint inhibitors, particularly in high-stemness melanoma models. The nanovaccine is shown to effectively target lymphatic vessels through the SR-BI receptor, enhancing its accumulation in lymph nodes and improving immune surveillance. The study also highlights the importance of nanoparticle properties such as core composition, particle size, surface charge, and surface modification in determining lymphatic targeting and DC uptake efficiency. The vaccine is safe and well-tolerated, with no observed liver or kidney toxicity, and has the potential for further clinical translation. The findings suggest that this HDL-mimetic nanovaccine represents a promising approach for personalized cancer immunotherapy.