Mechanisms of cancer cachexia and targeted therapeutic strategies

Tumor cachexia is a multifactorial syndrome characterized by systemic dysfunction, including anorexia and severe weight loss that is resistant to standard nutritional interventions. It is estimated that approximately 20 % of cancer patients succumb to cachexia in the later stages of their disease. Thus, understanding its pathogenesis is vital for improving therapeutic outcomes. Recent research has focused on the imbalance between energy intake and expenditure in cachexia. Clinically, cachexia presents with anorexia, adipose tissue atrophy, and skeletal muscle wasting, each driven by distinct mechanisms. Anorexia arises primarily from tumor-secreted factors and cancer-induced hormonal disruptions that impair hypothalamic regulation of appetite. Adipose tissue atrophy is largely attributed to enhanced lipolysis, driven by increased activity of enzymes such as adipose triglyceride lipase and hormone-sensitive lipase, coupled with decreased lipoprotein lipase activity. The browning of white adipose tissue, facilitated by uncoupling protein 1, further accelerates fat breakdown by increasing energy expenditure. Skeletal muscle atrophy, a hallmark of cachexia, results from dysregulated protein turnover via the ubiquitin-proteasome and autophagy-lysosomal pathways, as well as mitochondrial dysfunction. Additionally, chemotherapy can exacerbate cachexia. This review examines the molecular mechanisms underlying cancer cachexia and discusses current therapeutic strategies, aiming to inform future research and improve treatment approaches.