Vaccines are a promising immunotherapy that awakens the human immune system to inhibit and eliminate cancer with fewer side effects compared with traditional radiotherapy and chemotherapy. Although cancer vaccines have shown some efficacy, there are still troublesome bottlenecks to expand their benefits in the clinic, including weak immune effects and limited therapeutic outcomes. In the past few years, in addition to neoantigen screening, a main branch of the efforts has been devoted to promoting the lymph nodes (LNs) targeting of cancer vaccines and the cross-presentation of antigens by dendritic cells (DCs), two cardinal stages in effective initiation of the immune response. Especially, nanomaterials have shown hopeful biomedical applications in the improvement of vaccine effectiveness. This Review briefly outlines the possible mechanisms by which nanoparticle properties affect LN targeting and antigen cross-presentation and then gives an overview of state-of-the-art advances in improving these biological outcomes with nanotechnology.