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Glucose dependency of cancer cells can be targeted with a high-fat, low-carbohydrate ketogenic diet (KD). However, in IL-6-producing cancers, suppression of the hepatic ketogenic potential hinders the utilization of KD as energy for the organism. In IL-6-associated murine models of cancer cachexia, we describe delayed tumor growth but accelerated cachexia onset and shortened survival in mice fed KD. Mechanistically, this uncoupling is a consequence of the biochemical interaction of two NADPH-dependent pathways. Within the tumor, increased lipid peroxidation and, consequently, saturation of the glutathione (GSH) system lead to the ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impair corticosterone biosynthesis. Administration of dexamethasone, a potent glucocorticoid, increases food intake, normalizes glucose levels and utilization of nutritional substrates, delays cachexia onset, and extends the survival of tumor-bearing mice fed KD while preserving reduced tumor growth. Our study emphasizes the need to investigate the effects of systemic interventions on both the tumor and the host to accurately assess therapeutic potential. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer. [Display omitted] • Ketogenic diet delays tumor growth but accelerates cachexia and shortens survival • In the tumor, increased lipid peroxidation causes ferroptotic death of cancer cells • In the host, redox imbalance and NADPH depletion cause corticosterone deficiency • Dexamethasone plus ketogenic diet delays cachexia and preserves delayed tumor growth Ferrer et al. discover that the anti-cancer effects of a ketogenic diet are uncoupled from survival in mouse models of IL-6-producing cancers. Intratumoral ferroptosis causes a smaller tumor burden, but systemic NADPH depletion induces relative hypocorticosteronemia, which accelerates cachexia onset. These findings highlight the importance of considering both anti-cancer and host effects when investigating the outcome of systemic interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with cancer suffer from systemic metabolic impairment during cancer progression. An elevated neutrophil–lymphocyte ratio is a negative predictor of outcome. In the present study, we investigate a potential role of neutrophils on host metabolism. We identified widespread neutrophilia as an early event in cancer progression and found that neutrophils display an enhanced aerobic glycolytic profile. Pharmacological inhibition of aerobic glycolysis, a pathway that also characterizes cancer cells, leads to expanded neutrophilia, reduced tumor size, and shorter survival. Quantitative depletion of neutrophils impairs glucose homeostasis and the availability of hepatic lipids. Our results suggest that neutrophils play an adaptive role in metabolic host homeostasis during cancer progression and demonstrate that assessment of candidate cancer treatment efficacy should include both tumor and host responses. An elevated neutrophil–lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, using murine model systems of colorectal and pancreatic cancer we show that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, similar to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening the overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution, and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy. [ABSTRACT FROM AUTHOR]