Bruton's Tyrosine Kinase Inhibitors: Mechanisms, Efficacy, Toxicities and Applications for the Treatment of Human Diseases

ABSTRACT Bruton's tyrosine kinase (BTK) is a nonreceptor tyrosine kinase that couples B‐cell receptor (BCR) signaling to broader immune‐cell activation. By integrating signals from BCR, Toll‐like receptors, chemokine receptors, Fc receptors, and BAFF receptors, BTK governs B‐cell development, immune‐cell migration, innate immunity, and inflammation. Inhibition of BTK has transformed the treatment landscape of B‐cell malignancies, while the development of covalent, noncovalent, dual‐target inhibitors, and BTK degraders has expanded therapeutic opportunities. However, the mechanisms of action, resistance patterns, and expanding therapeutic applications of BTK inhibitors (BTKis) across malignant and nonmalignant diseases have yet to be comprehensively integrated. This review outlines BTK structure and signaling pathways, BTKi classification, resistance mechanisms, and emerging therapeutic strategies with emphasis on monotherapy in B‐cell malignancies and combination strategies involving CAR‐T therapy, immune checkpoint inhibitors, CD20‐targeted antibodies, BCL2 inhibitors, and hematopoietic stem cell transplantation. Mechanistically, these combinations enhance T‐cell function, attenuate immune checkpoint signaling, and remodel the tumor microenvironment (TME). We further discuss BTKis in solid tumors, autoimmune diseases, and chronic inflammatory disorders. Collectively, this review integrates current advances in BTK‐targeted therapy and highlights opportunities for precision treatment across oncology and immune‐mediated diseases.