The metabolic plasticity of cancer stem cells: bidirectional crosstalk with organ-resident cells

Cancer stem cells (CSCs), defined as tumor cell populations with self-renewal and tumor-propagating capacity, contribute to tumor initiation and participate in progression, therapeutic resistance and relapse through pronounced metabolic plasticity. Although CSC metabolism has traditionally been regarded as a cell-intrinsic feature, accumulating evidence highlights the tumor microenvironment as a critical determinant of CSC metabolic states. Diverse stromal and tissue-specific parenchymal cell populations actively shape metabolic niches through context-dependent interactions, thereby reinforcing CSC stemness and adaptive potential. This Review synthesizes current insights into how widespread and organ-specific tumor microenvironment cell populations reprogram CSC metabolism via bidirectional crosstalk. Such a framework provides a mechanistic basis for intratumoral and organ-context-dependent heterogeneity, as well as differential therapeutic responses. Finally, we discuss the emerging potential of targeting CSC-supportive metabolic niches through drug repurposing, highlighting context-aware metabolic interventions as a pragmatic strategy to overcome CSC-driven treatment resistance.