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

Abstract 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.