Personalized Multi‐Epitope Nanovaccine Unlocks B Cell‐Mediated Multiple Pathways of Antitumor Immunity

B lymphocytes have emerged as an important immune-regulating target. Inoculation with tumor cell membrane-derived vaccines is a promising strategy to activate B cells, yet their efficiency is limited due to lack of costimulatory molecules. To amplify B cell responses against tumor, herein, a spatiotemporally-synchronized antigen-adjuvant integrated nanovaccine, termed as CM-CpG-aCD40, is constructed by conjugating the immune stimulative CpG oligonucleotide and the anti-CD40 antibody (aCD40) onto the membrane vesicles derived from triple negative breast cancer cells. CM-CpG-aCD40 actively accumulates in lymph nodes and is effectively captured by antigen-presenting cells via the recognition of CD40 by aCD40. Tumor antigens on CM-CpG-aCD40 bind to B cell receptors, providing the first stimulation signal for B cells. Meanwhile, the interaction between CpG/Toll like receptor and aCD40/CD40 provides superposed co-stimulation signals, improving the antibody-secreting and antigen-presenting abilities of B cells. The nanovaccine also stimulates dendritic cells to activate CD8⁺ T cells, and reprograms tumor associated macrophages. CM-CpG-aCD40 activating humoral, cellular, and innate antitumor immunity achieves a tumor inhibition rate of 89.3%, which is further improved to 95.4% when combined with the anti-programmed death ligand 1 (PD-L1) antibody. CM-CpG-aCD40, as a personalized multi-epitope nanovaccine, paves the way for ushering the era of B cell-based immunotherapy.