Significance Current immunotherapies only benefit a minority of all cancer patients, so it is necessary to develop other strategies to boost patients’ antitumor CD8 ⁺ T cell responses. Here, we formulated a liposomal vaccine carrier that selectively delivers tumor antigens and Toll-like receptor agonists to human CD169/Siglec-1 ⁺ antigen-presenting cells (APCs) through the incorporation of gangliosides that are natural ligands of CD169. This liposomal vaccine binds to a variety of human CD169 ⁺ APCs, including monocyte-derived dendritic cells (moDCs) and the recently described Axl ⁺ DCs. Uptake of the vaccine results in robust cross-presentation and activation of tumor antigen-specific CD8 ⁺ T cells. Our findings demonstrate a unique vaccination platform by targeting human CD169 ⁺ DCs to stimulate antitumor T cell responses.