Effective　immune　responses　in　both　the　spleen　and　the　tumor　microenvironment　are　crucial　for　cancer　immunotherapy.　However,　delivery　of　neoantigen　peptide　vaccines　to　antigen-presenting　cells　(APCs)　at　these　sites　remains　challenging.　In　this　study,　LNPsD18,　a　cationic　liposomal　formulation　that　targets　and　enhances　APC　uptake　at　both　sites　without　modifying　the　targeting　ligands　is　developed.　By　co-delivering　tumor-specific　neoantigens　and　a　cholesterol-coupled　toll-like　receptor　9　(TLR9)　agonist　within　LNP-vaxD18,　an　approximately　60-fold　increase　in　dendritic　cell　uptake　compared　to　neoantigen-adjuvant　mixtures　is　achieved.　Intravenous　administration　of　the　liposome-neoantigen　peptide　vaccine　targets　both　the　spleen　and　the　tumor,　boosting　splenic　DC　activation,　increasing　M1-type　tumor-associated　macrophages,　and　elevating　tumor　cytokine　levels.　This　reshapes　the　tumor　microenvironment,　enhancing　IFN-γ-producing　CD8+　T　cells　and　TCF1+CD8+　T　cells　within　tumors.　These　outcomes　significantly　inhibit　established　tumor　growth　compared　to　nontargeted　lipid-based　nanovaccine　formulations,　resulting　in　improved　survival　in　orthotopic　hepatocellular　carcinoma　and　colorectal　cancer　models.　The　findings　highlight　the　importance　of　targeting　APCs　in　both　the　spleen　and　tumors　to　optimize　the　therapeutic　efficacy　of　liposome-neoantigen　vaccines　in　cancer　treatment.　©　2025　The　Author(s).　Advanced　Science　published　by　Wiley-VCH　GmbH.