<p>Cancer stem cells (CSCs) are a subpopulation of tumor cells with stem cell-like properties, which are endowed with unique self-renewal capacity and heterogeneity. Specifically, they drive tumor initiation, progression, recurrence, and therapeutic resistance. As the core drivers of tumor development and treatment resistance, CSCs exhibit distinct metabolic characteristics that sustain their self-renewal and differentiation potential. Various cells in the tumor microenvironment (TME) interact with CSCs, thereby creating a favorable niche for maintaining CSCs stemness. Furthermore, the metabolic patterns of CSCs themselves can modulate the functions of other TME-resident cells; collectively, these bidirectional interactions promote tumor recurrence and therapeutic resistance. A growing body of evidence has confirmed the critical role of CSCs in tumor progression, drug resistance, and recurrence, which lays a solid foundation for the development of potential therapeutic targets and intervention strategies. This review systematically summarizes the biological characteristics and targeted therapeutic strategies of CSCs, and explores potential directions to break through current therapeutic bottlenecks in combination with the latest status of clinical research.</p>