From pumps to networks: ABC transporters in leukemia resistance and microenvironmental adaptation.

ATP-binding cassette (ABC) transporters have long been recognized as critical mediators of multidrug resistance (MDR) in leukemia; however, emerging evidence reframes them as adaptive regulators within an integrated resistance network rather than static efflux pumps. This review consolidates recent mechanistic, functional, and translational insights into the role of key transporters, ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP), in drug resistance and microenvironmental adaptation. We describe how stress-responsive transcriptional programs (ATF4/JUN), stromal kinase signaling (PKC-NF-κB), and metabolic reprogramming (ABCC1-glutathione axis) dynamically regulate transporter expression and activity. Additionally, hypoxia/HIF-1α stabilization, lipid raft remodeling, and extracellular vesicle-mediated communication reinforce efflux competence and sustain leukemic stem cell persistence within protective bone marrow niches. Collectively, these data highlight a shift from isolated transporter overexpression toward network-driven multidrug resistance, wherein transcriptional, metabolic, and stromal inputs converge to reduce intracellular drug accumulation and promote relapse. The review also evaluates methodological standards for functional transporter assessment, including inhibitor-controlled efflux assays, and outlines therapeutic strategies targeting regulatory networks, such as stress-pathway inhibition, stromal disruption, and metabolic modulation, to attenuate adaptive efflux and enhance chemosensitivity. Understanding ABC transporters as components of a stress-responsive, microenvironment-integrated network provides a conceptual framework for developing transporter-aware, niche-adapted interventions aimed at overcoming leukemia resistance and achieving durable therapeutic remission.