The invention provides a hepatocellular carcinoma vaccine targeting secondary lymphoid tissues. The vaccine comprises fusion protein comprising (a) phosphatidylinositol proteoglycan-3 (GPC3) and (b) lymphocyte chemotactic factor (XCL1) polypeptide of a specifically bonded chemokine receptor 1 (XCR1), nucleic acid encoding the fusion protein and vectors of the nucleic acid, wherein (a) is connectedwith (b) through a linker, and (a) lacks amino acid residues with a cell membrane anchoring effect. The vaccine comprises the fusion protein, the nucleic acid and/or the vectors, and application of the fusion protein, the nucleic acid and/or the expression vectors in prevention and treatment of liver cancers is provided. The vaccine has the effect of intervention of generation and development ofliver cancers, and can be applied to intervention of high-risk population of liver cancer, and for example, the vaccine can be applied to intervention of the generation progress of hepatitis B-relatedpatients to liver cancers.