Gemcitabine resistance in gallbladder cancer: mechanistic insights with emphasis on cancer stem cells

Gemcitabine remains the primary chemotherapeutic agent for multiple solid tumours; however, the development of resistance greatly limits its effectiveness. This resistance is multifactorial, including mechanisms affecting intracellular drug concentration, enhancement of DNA repair mechanisms, evasion of apoptosis, and others. Increasing evidence suggests that cancer stem cells (CSCs) play a key role in driving gemcitabine chemoresistance. CSCs show intrinsic features such as quiescence, enhanced DNA repair, epithelial–mesenchymal transition (EMT) traits, and overexpression of drug efflux transporters, all of which help them survive gemcitabine treatment. Additionally, dysregulated signalling pathways like Hedgehog, Notch, Wnt/β-catenin, and PI3K/AKT/mTOR are closely linked to CSC maintenance and gemcitabine resistance. The tumour microenvironment further supports CSC survival through hypoxia, stromal interactions, and cytokine signalling, creating a protective niche that reduces drug effectiveness. Understanding how CSCs contribute to gemcitabine resistance opens up new treatment options, such as targeting CSC markers (CD44, CD24, EpCAM, ALDH1), modulating abnormal signalling pathways, and using combination strategies to eliminate both bulk tumour cells and CSCs. This review emphasizes the clinical importance of CSCs in mediating gemcitabine resistance and underscores the need for CSC-targeted therapies to improve patient outcomes.