CAR design equips diverse immune cells with unique antigen-specific activation identities

In parallel, CAR-engineering has extended beyond T cells, which have achieved success in treating B cell malignancies, to broader immune cell types alongside cell type-specific CAR design. However, how CAR architecture modulates activation phenotypes across immune lineages remains poorly understood.

Here, we systematically compared previously validated, immune cell-optimised CARs across immune cell types using a human HSPC-derived multilineage CAR-immune cell platform. HSPC-derived T, NK and myeloid cells demonstrated immune activation across different CAR designs whereas cell-specific activation showed CAR design dependency in B cells. Hallmark pathway analysis revealed that immune lineage was the dominant determinant of activation-induced transcriptional states while CAR design modulated signalling programmes within lineage constrained programmes, notably proliferation, inflammation and cytokine responses.