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

www.nature.com/emm REVIEW ARTICLE OPEN The metabolic plasticity of cancer stem cells: bidirectional crosstalk with organ-resident cells Junseok Jang1,2, Minseo Gwak1,2 and Hyunggee Kim1 ✉ © The Author(s) 2026 1234567890();,: 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. Experimental & Molecular Medicine; https://doi.org/10.1038/s12276-026-01746-8 INTRODUCTION Tumors are heterogeneous diseases composed of hierarchical layers of cellular populations that function as a complex ecosystem. Driven by remarkable plasticity that enables genetic, phenotypic and functional reprogramming, cancer stem cells (CSCs) orchestrate tumor initiation, metastatic progression, therapeutic resistance and relapse, while adapting to and persisting in hostile conditions1,2. Despite their central role in tumor biology, establishing a precise, universally accepted definition of CSCs remains challenging, largely due to the lack of common markers consistently applicable across tumor types and organs. Therefore, in this Review, CSCs are operationally defined as tumor cell populations that possess self-renewal capacity while maintaining sufficient plasticity under microenvironmental or therapeutic pressures. Among the functional hallmarks that characterize CSCs, metabolic plasticity underpins the entire disease process, serving as a central force that enables CSCs to adapt and survive across diverse tumor microenvironments (TMEs). Targeting CSC metabolism therefore represents a promising therapeutic strategy, given its critical role in maintaining tumorpropagating potential and stem-like traits associated with malignancy (Fig. 1). In this context, repurposing metabolic drugs for cancer therapy offers a valuable opportunity for rapid clinical translation, supported by established safety profiles, cost-effectiveness, broad availability and suitability for long-term use. However, metabolic inhibitors exhibit variable anticancer efficacy across tumor types and often exert their effects through off-target mechanisms rather than their original modes of action. A recent review of clinical and preclinical repurposing studies reported that, among eight antihypertensive and six antidiabetic drugs evaluated for cancer therapy, only epalrestat demonstrated consistent ontarget activity across multiple cancers by targeting AKR1B1/ AKR1B10, the same molecular targets implicated in diabetes3. This limited efficacy of reliable metabolic targeting probably reflects both intratumoral heterogeneity and organ-context-dependent heterogeneity. In this Review, we address both intratumoral heterogeneity arising from CSC plasticity and niche interactions within individual tumors and organ-context-dependent heterogeneity, which reflects differences in metabolic programs across tumors originating in distinct organ environments. Consequently, the TME, particularly the metabolic interactions between CSCs and stromal as well as tissue-specific parenchymal cell populations, emerges as a key determinant of therapeutic response. In this Review, we focus on how stromal and tissue-specific parenchymal cell populations actively reprogram CSC metabolism within the TME. By dissecting tissue-defined metabolic niches and their context-dependent effects on CSCs, we aim to provide mechanistic insights that may reveal actionable, tumor-typespecific metabolic vulnerabilities. Ultimately, elucidating the complex cell–cell interactions that regulate CSC metabolism is crucial for overcoming the inter- and intratumoral heterogeneity that currently limits effective treatment strategies. UBIQUITOUS TME CELL TYPES THAT DRIVE INTRATUMORAL METABOLIC HETEROGENEITY Commonly observed across most solid tumors, specific TME cell types are broadly distributed throughout the body to systemically influence metabolic programs while simultaneously adapting to local tumor environments, thereby contributing to intratumoral Department of Biotechnology, Korea University, Seoul, Republic of Korea. 2These authors contributed equally: Junseok Jang, Minseo Gwak. ✉email: 1 Received: 27 January 2026 Revised: 24 March 2026 Accepted: 26 March 2026 J. Jang et al. 2 Fig. 1 Metabolic plasticity supporting CSC adaptability and stemness within the TME. Within the TME, CSCs are exposed to various signals from immune cells, stromal cells, organ-specific parenchymal cells and other environmental factors. In response, CSCs actively engage in interconnected metabolic pathways, including redox balance, adaptive glucose and energy metabolism, lipid metabolism, amino acid metabolism and epigenetic–metabolic crosstalk, to support metabolic adaptation and maintain stemness. This figure offers a conceptual framework summarizing the key metabolic features of CSCs that collectively enable their adaptability and persistence within diverse TME. AcCoA, acetyl-coenzyme A; Arg, arginine; α-KG, α-ketoglutarate; Cys, cysteine; Gln, glutamine; Lys, lysine; Met, methionine; NAD, nicotinamide adenine dinucleotide; PPP, pentose phosphate pathway; SAM, S-adenosyl-L-methionine. Figure created in BioRender. Jang, J. (2026) https:// BioRender.com/e9f60xu. heterogeneity. These cells perform essential functions—including immune regulation, stromal remodeling and angiogenesis—that collectively establish the metabolic framework of the TME (Fig. 2). Importantly, this framework is not static but is dynamically reshaped by spatial organization, metabolic stress and cellular interactions within tumors, resulting in localized metabolic niches that influence CSC states and therapeutic responses. While bulk tumor studies typically address whether an individual metabolic pathway promotes tumor growth, research focused on CSC-centered metabolic interactions emphasizes the integration of metabolic and stemness programs. Accordingly, accumulating evidence highlights the importance of context (...truncated)