{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Bruton's tyrosine kinase (BTK) is a multifunctional enzyme that plays central roles in both adaptive and innate immune signaling. In B cells, BTK is a critical mediator of B‐cell receptor (BCR) signaling, where it promotes cell survival, proliferation, and migration. This function is exemplified in chronic lymphocytic leukemia (CLL), where BTK overexpression and its constitutive activation sustain malignant growth, and inhibition of BTK with agents such as ibrutinib (an irreversible inhibitor) or PCI‐32765 disrupts these pro‐survival pathways. However, acquired resistance to ibrutinib—for example, via mutation of a key binding cysteine residue—has been documented, and new strategies (including PROteolysis TArgeting Chimeras) have been developed to target both wild‐type and mutant BTK."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its canonical role in BCR signaling, BTK also has important functions in innate immunity. It interacts with Toll-like receptors (TLRs) and their adaptor proteins—including MyD88 adapter–like protein (Mal)—to propagate signals leading to NF-κB activation and cytokine modulation. BTK’s involvement in TLR-mediated pathways is illustrated by its binding to multiple TLR family members and its capacity to phosphorylate Mal, thereby influencing downstream inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, BTK can form complexes with other signaling proteins to reinforce oncogenic pathways. For example, in Waldenström macroglobulinemia, BTK associates with mutant MYD88, which sustains NF-κB activation and malignant cell survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n BTK’s functional repertoire also extends to non–B-cell lineages. In osteoclasts, BTK cooperates with Tec kinases within a signaling complex that couples receptor activator of NF-κB (RANK) and immunoreceptor tyrosine-based activation motif (ITAM)-dependent cues to mediate differentiation and bone resorption."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Moreover, in platelets, BTK participates in integrin and collagen receptor signaling required for firm adhesion and aggregation, with its inhibition by ibrutinib contributing to bleeding complications observed in a subset of patients."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, BTK-regulated pathways contribute to the modulation of the tumor microenvironment. In pancreatic ductal adenocarcinoma (PDAC), for instance, BTK signaling in B cells and macrophages fosters T-cell suppression, and its inhibition reprograms these cells to support antitumor immunity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In ex vivo studies of CLL, BTK inhibition sensitizes malignant cells to apoptosis, particularly when used in combination with agents targeting antiapoptotic proteins."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore BTK as a pivotal kinase that integrates signals from the B-cell receptor, toll-like receptors, and other cell surface receptors to regulate immune cell development, survival, and inflammatory responses. Its diverse roles highlight why BTK is an attractive therapeutic target in a range of disorders, from B-cell malignancies to immune-mediated and inflammatory diseases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jennifer A Woyach, Richard R Furman, Ta-Ming Liu, et al. 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