Advances and resistance adaptation in BTK-targeted therapy for B-cell malignancies.

Bruton's tyrosine kinase (BTK) is a key signaling component downstream of the B-cell receptor (BCR) and plays an essential role in the survival and proliferation of multiple B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström macroglobulinemia (WM). BTK inhibitors (BTKi) have demonstrated substantial clinical benefit and are now widely incorporated into frontline treatment strategies. However, the long-term effectiveness of BTKi is frequently limited by the emergence of both intrinsic and acquired resistance. BTKi resistance reflects a dynamic process of cellular adaptation rather than a single dominant mechanism. Malignant B cells maintain viability under BTK inhibition through multiple, interconnected alterations, including changes in BTK structure or function, reprogramming of proximal BCR signaling, activation of alternative survival pathways, tumor microenvironment-mediated immune modulation, and metabolic and epigenetic remodeling. In this review, we summarize recent advances in BTK-targeted therapeutics and present a mechanistic framework for understanding BTKi resistance as an adaptive and context-dependent process. We discuss emerging resistance mechanisms that extend beyond canonical signaling pathways and review therapeutic strategies aimed at addressing these adaptive responses, including non-covalent BTK inhibitors, BTK degraders, and rational combination regimens. This perspective highlights translational strategies to improve the depth and durability of responses to BTK-targeted therapies.