Resistance to covalent Bruton's tyrosine kinase inhibitors in diffuse large B‑cell lymphoma: Molecular mechanisms and therapeutic implications (Review)

B‑cell receptor (BCR) signaling is essential for the survival and proliferation of normal B cells, and contributes substantially to the pathogenesis of diffuse large B‑cell lymphoma (DLBCL). Bruton's tyrosine kinase (BTK), a key downstream component of the BCR pathway, has emerged as an important therapeutic target in B‑cell malignancies. However, the clinical efficacy of BTK inhibitors (BTKi) in DLBCL remains heterogeneous and is strongly influenced by molecular subtype and signaling dependency. Accumulating evidence indicates that BTKi resistance in DLBCL is driven by diverse molecular mechanisms, including BTK mutations, gain‑of‑function alterations in phospholipase Cγ2, activation of the caspase recruitment domain family member 11‑B‑cell lymphoma/leukemia 10‑mucosa‑associated lymphoid tissue lymphoma translocation protein 1 complex and dysregulation of myeloid differentiation primary response 88, cluster of differentiation 79B, tumor necrosis factor‑α‑induced protein 3 and Kelch‑like protein 14. In addition to these genetic determinants, non‑genetic adaptive mechanisms, such as compensatory phosphoinositide 3‑kinase/AKT/mechanistic target of rapamycin and mitogen‑activated protein kinase/extracellular signal‑-regulated kinase signaling, epigenetic reprogramming, tumor microenvironment remodeling, metabolic rewiring and endoplasmic reticulum stress, may further contribute to therapeutic escape. Emerging approaches, including next‑generation covalent and non‑covalent BTKi, dual‑mode inhibitors, BTK‑targeting degraders, allosteric inhibitors and multi‑target strategies, are currently being investigated as potential strategies to address BTKi resistance. The present review summarized the molecular mechanisms underlying BTKi resistance in DLBCL and discussed their potential implications for biomarker development, rational combination therapy and future precision treatment.