Mechanisms of resistance to bruton’s tyrosine kinase inhibitors: synergistic effects of tumor microenvironment regulation and signaling pathways

It is widely acknowledged that B-cell lymphoma represent a significant threat to human health, and Bruton Tyrosine Kinase inhibitors (BTKi) have been shown to exhibit superior clinical efficacy and safety in comparison to conventional chemotherapy and immunotherapy modalities. However, as patients continue to use BTKi over a time, they will inevitably encounter the drug resistance. This resistance renders the therapeutic efficacy of BTKi, thereby significantly constraining its clinical benefits. Drug resistance of tumor is a multifaceted process influenced by numerous factors, mainly including individual genetic variations, tumor stem cells, drug inactivation, reduced drug absorption, and altered metabolism of anti-tumor drugs. The tumor microenvironment (TME) has been demonstrated to exert an important influence on the process of therapy resistance. It is evident that non-cellular components (e.g. the extracellular matrix, hypoxia, an acidified microenvironment, exosome, and cytokines) modulate the drug resistance through different mechanisms. These mechanisms include physical barriers that impede drug delivery, the formation of an immunosuppressive microenvironment, metabolic reprogramming and the activation of bypass signal moueculars. Furthermore, the presence of mutations of moleculars involved in the BCR signaling pathways (e.g. BTK and PLCG2 mutations) and the aberrant activation of key pathways such as PI3K-AKT-mTOR, NF-κB, Wnt/β-catenin and MAPK/ERK signaling further weakened the efficacy of BTKi. This review focus on the mechanism of BTKi resistance, the role of the TME and its components in drug resistance. It emphasized that targeting TME remodeling and combined the inhibition of multiple pathways may provide a new strategy for overcoming drug resistance, optimizing the treatment paradigm of B-cell lymphoma.