Autophagy-related gene 5 in drug resistance: a comprehensive review

ATG5 (Autophagy-Related Gene 5) is a central regulator of cellular autophagy and a critical node at the intersection of autophagy, apoptosis and therapy resistance. Beyond its canonical role in autophagosome formation, ATG5 engages key apoptotic regulators and multiple signaling pathways to shape cancer cell fate. Although ATG5 is ubiquitously expressed in normal tissues, its impact in cancer is highly context specific. In numerous solid tumors, high ATG5 expression is associated with worse overall survival and therapy resistance, whereas in other cancer types elevated ATG5 predicts improved outcomes, reflecting its capacity to act as either a tumor suppressor or a tumor-protective factor. In this Review, we synthesize current knowledge on ATG5 as a context-dependent molecular switch that reshapes the balance between cellular adaptation and therapeutic vulnerability. We map the signaling networks that crosstalk with ATG5 to sustain autophagy-dependent survival and rewire stress responses to promote drug resistance across therapeutic modalities. We further delineate the regulatory and protein-interaction interfaces that maintain this dependency, and the treatment contexts in which autophagy inhibition is most likely to be effective. Together, these insights position ATG5 as both a mechanistic linchpin in therapy resistance and a translational opportunity. Defining tumors that are functionally dependent on ATG5-mediated autophagy, and the specific interactome nodes that sustain this state, will be essential for developing biomarker-driven strategies that convert ATG5 dependence into a therapeutic vulnerability.