Multidimensional Roles of the Transcription Factor EB-Regulated Autophagy-Lysosomal Network in Tumor Drug Resistance

Chemotherapy resistance is a key factor in tumor recurrence and mortality and a barrier to durable therapeutic effectiveness. Besides canonical mechanisms, including target alterations and drug efflux, tumor cells integrate chemotherapy-induced DNA damage, oxidative stress, and metabolic stress into persistent adaptive stress-response programs in which the autophagy-lysosomal pathway (ALP) plays a pivotal role. Transcription factor EB (TFEB), a master transcriptional regulator of the ALP, undergoes stress-responsive nuclear translocation under chemotherapeutic conditions through mechanistic target of rapamycin complex 1 (mTORC1) inhibition, lysosomal Ca²⁺-calcineurin-mediated dephosphorylation, and related signaling cascades. Nuclear TFEB activates the canonical coordinated lysosomal expression and regulation (CLEAR) network while also engaging broader context-dependent transcriptional programs. Within the autophagy-lysosomal system, CLEAR-dependent regulation promotes autophagosome biogenesis and maturation, autophagosome-lysosome fusion, and lysosomal biogenesis, resulting in enhanced autophagic flux. TFEB-driven enhancement of ALP flux generates multiple adaptive functional outputs, including clearance of damaged cellular substrates, buffering of reactive oxygen species (ROS), recycling of metabolic substrates to meet bioenergetic demands, modulation of cell death thresholds, and reduced effective intracellular drug exposure via lysosomal sequestration, storage, efflux, and intracellular redistribution. This review presents an integrated conceptual platform linking stress-induced TFEB activation, enhanced autophagic flux, downstream functional adaptations, and the emergence of chemotherapeutic resistance. By focusing on the TFEB-ALP axis, this review further identifies a stratified therapeutic intervention model comprising upstream suppression, intermediate pathway blockade, and downstream functional counteraction. These perspectives provide a more systematic and mechanistic understanding for developing precision strategies to overcome chemotherapy resistance by targeting the TFEB-ALP axis.