Autophagy in cancer cachexia: From mechanisms to therapeutic opportunities

Cancer cachexia is a multifactorial syndrome characterized by body weight loss, muscle wasting, and systemic metabolic alterations, significantly contributing to patient morbidity and mortality. A key feature of cachexia is the excessive degradation of muscle proteins and mitochondria, largely mediated by autophagy. Although hyperactivation of autophagy has been widely recognized as a hallmark of cancer cachexia, its precise role in exacerbating muscle atrophy through enhanced proteolysis and mitochondrial disposal remains a subject of ongoing debate. This review provides a comprehensive overview of previous milestones and recent advancements in understanding autophagy's role in cancer cachexia, with particular focus on its impact on skeletal muscle and liver, as well as its contribution to tumor metabolic flexibility. Additionally, the review explores emerging therapeutic strategies aimed at modulating autophagy, including exercise, exercise mimetics, and novel molecules to selectively target specific branches of autophagy. By synthesizing current evidence, this review highlights the need for further research into the mechanisms underlying autophagy dysregulation in cancer cachexia and the potential for autophagy-based interventions to improve patient outcomes.