Unraveling the underlying mechanisms of cancer stem cells in therapeutic resistance for optimizing treatment strategies

The success of cancer therapy has been significantly hampered by various mechanisms of therapeutic resistance. Chief among these mechanisms is the presence of clonal heterogeneity within an individual tumor mass. The introduction of the concept of cancer stem cells (CSCs)—a rare and immature subpopulation with tumorigenic potential that contributes to intratumoral heterogeneity—has deepened our understanding of drug resistance. Given the characteristics of CSCs, such as increased drug-efflux activity, enhanced DNA-repair capacity, high metabolic plasticity, adaptability to oxidative stress, and/or upregulated detoxifying aldehyde dehydrogenase (ALDH) enzymes, CSCs have been recognized as a theoretical reservoir for resistant diseases. Implicit in this recognition is the possibility that CSC-targeted therapeutic strategies might offer a breakthrough in overcoming drug resistance in cancer patients. Herein, we summarize the generation of CSCs and our current understanding of the mechanisms underlying CSC-mediated therapeutic resistance. This extended knowledge has progressively been translated into novel anticancer therapeutic strategies and significantly enriched the available options for combination treatments, all of which are anticipated to improve clinical outcomes for patients experiencing CSC-related relapse.