Dietary serine and glycine restriction delays cancer-associated cachexia

Cancer cachexia is a severe metabolic complication of malignancy characterized by loss of appetite, progressive tissue wasting leading to adipose tissue and/or muscle loss and systemic inflammation. Energy dysregulation and nutrient availability are increasingly recognized as key determinants of host metabolic adaptation during tumour progression. However, how diets can be used to support the host remains unclear and conventional dietary regimes have failed to reverse cancer cachexia. Here, we show that dietary serine/glycine restriction induces a coordinated host metabolic reprogramming that delays the onset of cachexia in tumour-bearing mice. Healthy mice fed a serine/glycine free diet show modest body weight loss resulting from reduced caloric intake and reduced adiposity. Surprisingly, in cancer bearing mice, the remodelled metabolic state leads to preservation of adipose depots and delayed cancer associated cachexia. This response is independent of the impact of serine availability on tumour growth, suggesting that it is the result of host-driven adaptations rather than a direct reflection of tumour burden. Mechanistically, we show that serine and glycine restriction remodels systemic metabolism, leading to reduced oxidative lipid stress and attenuation of inflammatory responses. Together, these findings identify serine/glycine availability as a key regulator of host metabolic resilience during cancer progression. These data support a model in which dietary amino acid restriction modulates systemic inflammation and lipid metabolism to delay the onset of cachexia, highlighting potential therapeutic avenues aimed at targeting host metabolic state rather than tumour growth alone.