Cancer stem cells and drug resistance in cancer: molecular mechanisms and therapeutic targets

Abstract

Cancer therapy has advanced substantially through targeted therapies and immunotherapy; however, durable clinical responses remain limited by the development of drug resistance. Increasing evidence identifies cancer stem cells (CSCs) as central drivers of therapeutic failure, tumor recurrence, metastasis, and minimal residual disease. CSCs possess self-renewal and differentiation capacities together with remarkable adaptability under therapeutic stress, enabling long-term tumor maintenance and regeneration. CSC-mediated resistance arises through coordinated intrinsic and extrinsic mechanisms. Intrinsically, CSCs employ multiple survival programs, including cellular quiescence, enhanced DNA damage response and repair, ATP-binding cassette transporter-mediated drug efflux, apoptosis evasion, and metabolic reprogramming. Extrinsically, these mechanisms are reinforced through dynamic interactions with the tumor microenvironment (TME), particularly hypoxic and perivascular niches that support stemness and therapeutic tolerance. Importantly, CSCs are increasingly recognized as dynamic cellular states rather than fixed populations and exhibit marked plasticity through reversible transitions between stem-like and non-stem states, frequently mediated by epithelial–mesenchymal transition (EMT). This plasticity promotes intratumoral heterogeneity and replenishes resistant cell populations. In this review, we provide a comprehensive synthesis of the molecular and microenvironmental mechanisms underlying CSC-driven drug resistance and critically discuss emerging therapeutic strategies targeting CSC plasticity, niche interactions, metabolic adaptation, and immune evasion. Collectively, these insights support the development of integrated multi-target therapeutic approaches to improve long-term clinical outcomes.