The Immunomodulatory Mechanisms of BTK Inhibition in CLL and Beyond

Bruton's tyrosine kinase (BTK), a cytoplasmic tyrosine kinase, plays a pivotal role in B cell biology and function. As an essential component of the B cell receptor (BCR) signaling pathway, BTK is expressed not only in B cells but also in myeloid cells, including monocytes/macrophages, dendritic cells, neutrophils, and mast cells. BTK inhibitors (BTKis) have revolutionized the treatment of chronic lymphocytic leukemia (CLL) and other B cell malignancies. Besides their well-characterized role in inhibiting BCR signaling, BTKis also exert significant immunological influences outside the tumor cell that extend their therapeutic potential and impact on the immune system in different ways. This work elucidates the immunomodulatory mechanisms associated with BTK inhibition, focusing on CLL and other clinical contexts. We discuss how BTK inhibition affects various immune cells, including B cells, T cells, and macrophages. The effects of BTKis on the profiles of cytokines, also fundamental parts of the tumor microenvironment (TME), are summarized here as well. This review also appraises the implications of these immunomodulatory actions in the management of autoimmune diseases and infections. Summarizing the dual role of BTK inhibition in modulating malignant lymphocyte and immune cell functions, this paper highlights the broader potential clinical use of compounds targeting BTK.