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By integrating signals from BCR, Toll\u2010like receptors, chemokine receptors, Fc receptors, and BAFF receptors, BTK governs B\u2010cell development, immune\u2010cell migration, innate immunity, and inflammation. Inhibition of BTK has transformed the treatment landscape of B\u2010cell malignancies, while the development of covalent, noncovalent, dual\u2010target 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\u2010cell malignancies and combination strategies involving CAR\u2010T therapy, immune checkpoint inhibitors, CD20\u2010targeted antibodies, BCL2 inhibitors, and hematopoietic stem cell transplantation. Mechanistically, these combinations enhance T\u2010cell 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\u2010targeted therapy and highlights opportunities for precision treatment across oncology and immune\u2010mediated diseases.<\/jats:p>","DOI":"10.1002\/mco2.71029","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T07:06:30Z","timestamp":1790924790000},"source":"Crossref","is-referenced-by-count":0,"title":["Bruton's Tyrosine Kinase Inhibitors: Mechanisms, Efficacy, Toxicities and Applications for the Treatment of Human Diseases"],"prefix":"10.1002","volume":"7","author":[{"given":"Miao","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Hematology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dengju","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hematology, Tongji Hospital, Tongji Medical College Huazhong University of 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