Cancer-associated cachexia — understanding the tumour macroenvironment and microenvironment to improve management

Cachexia is a devastating, multifactorial and often irreversible systemic syndrome characterized by substantial weight loss (mainly of skeletal muscle and adipose tissue) that occurs in around 50–80% of patients with cancer. Although this condition mainly affects skeletal muscle (which accounts for approximately 40% of total body weight), cachexia is a multi-organ syndrome that also involves white and brown adipose tissue, and organs including the bones, brain, liver, gut and heart. Notably, cachexia accounts for up to 20% of cancer-related deaths. Cancer-associated cachexia is invariably associated with systemic inflammation, anorexia and increased energy expenditure. Understanding these mechanisms is essential, and the progress achieved in this area over the past decade could help to develop new therapeutic approaches. In this Review, we examine the currently available evidence on the roles of both the tumour macroenvironment and microenvironment in cancer-associated cachexia, and provide an overview of the novel therapeutic strategies developed to manage this syndrome. Cachexia is a multi-organ syndrome characterized by substantial weight loss that affects a majority of patients with cancer and contributes to cancer-related mortality. The authors of this Review discuss the contribution of both the tumour macroenvironment and microenvironment to the inflammatory and metabolic processes involved in cancer-associated cachexia and provide an overview of the therapeutic strategies developed to manage this syndrome. Key points Cachexia is a wasting syndrome characterized by weight loss (both skeletal muscle and adipose tissue), anorexia and inflammation that commonly occurs in patients with cancer and contributes substantially to cancer-related mortality. Both the macroenvironment and the microenvironment contribute to the inflammatory process that characterizes cancer-associated cachexia; new therapeutic approaches must effectively target these mechanisms. International guidelines for the management of patients with cancer-associated cachexia strongly recommend promoting anabolism and reducing catabolism through nutritional, physical and pharmacological interventions. The development of new therapeutic approaches to the prevention of low skeletal muscle mass in patients with cancer-associated cachexia is an unmet need that can be addressed through multidisciplinary collaborations involving, among others, oncologists, radiologists, surgeons, nutritionists, di