Comprehensive review of drug resistance in mammalian cancer stem cells: implications for cancer therapy.

Cancer remains a significant global challenge, and despite the numerous strategies developed to advance cancer therapy, an effective cure for metastatic cancer remains elusive. A major hurdle in treatment success is the ability of cancer cells, particularly cancer stem cells (CSCs), to resist therapy. These CSCs possess unique abilities, including self-renewal, differentiation, and repair, which drive tumor progression and chemotherapy resistance. The resilience of CSCs is linked to certain signaling pathways. Tumors with pathway-dependent CSCs often develop genetic resistance, whereas those with pathway-independent CSCs undergo epigenetic changes that affect gene regulation. CSCs can evade cytotoxic drugs, radiation, and apoptosis by increasing drug efflux transporter activity and activating survival mechanisms. Future research should prioritize the identification of new biomarkers and signaling molecules to better understand drug resistance. The use of cutting-edge approaches, such as bioinformatics, genomics, proteomics, and nanotechnology, offers potential solutions to this challenge. Key strategies include developing targeted therapies, employing nanocarriers for precise drug delivery, and focusing on CSC-targeted pathways such as the Wnt, Notch, and Hedgehog pathways. Additionally, investigating multitarget inhibitors, immunotherapy, and nanodrug delivery systems is critical for overcoming drug resistance in cancer cells.