Antigen-independent BCR signals limit differentiation and survival of IgM antibody-secreting cells

IgM contributes to early and durable humoral immunity, yet the mechanisms governing human IgM plasma cell (PC) maturation and persistence remain unknown. Here, using an ex vivo human B cell system, we found that IgM B cell receptor (BCR) signaling restricts IgM antibody-secreting cell (ASC) differentiation and survival. Using CRISPR-mediated gene disruption and pharmacologic inhibition, we show that surface BCR and its proximal signaling components, particularly SYK, suppressed induction of IRF4 and PRDM1, thereby restraining PC differentiation. Concurrently, ligand-independent BCR signaling increased basal calcium flux and apoptosis in IgM plasmablasts. Inhibition of BCR-proximal signaling also increased PC numbers and persistence after in vivo engraftment. Leveraging this mechanistic insight, we demonstrated that SYK KO in engineered PCs (ePCs) significantly improved output and in vivo durability of IgM-cetuximab-secreting ePCs. Together, these findings reveal IgM-BCR signaling as a previously unrecognized negative regulator of human IgM PC differentiation and survival and show that inhibition of BCR-proximal pathways can improve IgM-based cellular immunotherapies.