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The cortex fuels essential physiological processes with glucose-derived carbon, while gliomas fuel their aggressiveness by rerouting glucose carbon pathways and scavenging alternative carbon sources such as environmental amino acids, providing a potential therapeutic target.

The molecular mechanisms of mitochondrial dysfunction in the premature ageing Werner syndrome were elusive. Here the authors show that NAD⁺ depletion-induced impaired mitophagy contributes to this phenomenon, shedding light on potential therapeutics.

Hypoxia induces ·NO-dependent hydrogen sulfide (H₂S) biogenesis by inhibiting the transsulfuration pathway. H₂S oxidation promotes endothelial cell proliferation to support neovascularization in tissue injury and tumor xenograft models.

A study of human and mouse models of pancreatic cancer finds that inhibiting the lipid kinase PIKfyve interferes with the cancer’s lipid homeostasis, making it a potential target for drug development.

Using a genome-wide CRISPR knock-out screen, the authors defined the repertoire of genes that are required for proerythroblast survival and for terminal erythroid differentiation.

Fructose and glucose have the same caloric value, but the two sugars are metabolized differently. It emerges that mice that cannot metabolize fructose are healthier when placed on carbohydrate-rich diets.

Halbrook et al. report two metabolic subgroups of pancreatic ductal adenocarcinoma cells defined by differential integrated stress response and asparagine production that permit symbiosis and phenformin resistance.

The aspartate aminotransaminase GOT1 is important for maintaining redox balance. Here, the authors show that inhibition of GOT1 in pancreatic cancer cells leads to cell death via ferroptosis.

A metabolite screen of pancreatic cells shows that pancreatic cancer cells metabolize uridine-derived ribose via UPP1, supporting redox balance, survival and proliferation.

Pediatric brain cancers are lethal malignancies driven by less-differentiated stem-like cells. Here the authors show that these cells exhibit distinct mitochondrial metabolism programs with targetable vulnerabilities.

In a pilot feasibility study involving recipients of allogeneic hematopoietic stem cell transplants, adherence to a dietary intervention and its effects on the gut microbiota were assessed in the run-in to a study testing the effects of modulation of the microbiome on transplant outcomes.

Response to chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC) is often limited. Here, the authors report improved response to chemotherapy in PDAC patients with hyperglycaemia and investigate the underlying mechanism via glucose-mediated disruption of redox metabolism

Cancer cells can be dependent on mitochondrial respiration to survive. Here, in pancreatic cancer cells, the authors show that monounsaturated fatty acids-linked ether lipids maintain mitochondrial redox homeostasis and modulate sensitivity to inhibition to electron transport chain complex I.

Stem cell quiescence is generally considered as an inactive state with poised potential. Here, Khoa et al. find that quiescent embryonic stem cells actively maintain a dynamic reservoir of cells with unrestricted cell fate that converges on S-adenosylmethionine and H3K27me3 status.

Tumor fibrosis is known to suppress anti-tumor immunity. A new study now highlights the role of tumor-associated macrophages in coordinating fibrosis-mediated metabolic changes in tumors, restricting cytotoxic T cell responses and contributing to tumor growth.

Watson et al. demonstrate that astrocyte mitochondria can be horizontally transferred to glioblastoma cells in a GAP43-dependent manner, leading to changes in mitochondrial respiration and metabolism that promote proliferation and tumor growth.

Targeting genotype-independent abnormalities may overcome therapy resistance in glioblastoma despite intratumoral genomic heterogeneity. Here, the authors show that glioblastoma radiation resistance is promoted by purine metabolism and can be overcome by inhibitors of purine synthesis.

Pancreatic cancers use a novel glutamine metabolism pathway, regulated by oncogenic KRAS, to maintain redox balance; these findings add to the understanding of the mechanisms by which oncogenic alterations reprogram cellular metabolism to promote tumour growth.

Gene-expression profiles from over 1,000 colorectal tumors define six subtypes with specific phenotypical features, responses to therapy and clinical progression.

Winter and colleagues demonstrate that metabolic adaptation to nutrient stress in the tumor microenvironment of pancreatic cancer leads to a dependency on IDH1, which is therapeutically actionable regardless of IDH1 mutation status.

Agnihotri and colleagues show that loss of the MAT2A enzyme of the methionine cycle induces a global depletion of H3K36me3 and extends survival in glioma models, representing a potential therapeutic vulnerability.

Expression of the transporter SLC43A2 by tumour cells allows them to outcompete T cells for methionine and thereby disrupt the survival and function of tumour-infiltrating T cells.

Ferraro et al. report that fatty acid synthesis is needed for brain cancer metastasis and show that blocking this process by inhibiting fatty acid synthase reduces the metastatic growth of breast cancer cells in the brain.

Using patient-derived colorectal cancer tumour enteroids, Schwartz et al. find that ectopic expression of hepcidin in the tumour epithelium establishes an axis to sequester iron to maintain the nucleotide pool and sustain proliferation.

Intestinal epithelial cell (IEC) damage by T cells contributes to alloimmune, autoimmune and iatrogenic diseases such as graft-versus-host and inflammatory bowel disease. Here the authors identify a critical role for the alteration of the IEC-specific mitochondrial complex II component succinate dehydrogenase A in the regulation of the severity of T cell-mediated intestinal diseases.

Recent technological advances permit the profiling of metabolic changes in single cells, which sheds light on how metabolism regulates immune responses. We advocate for accessible and standardized tools to reduce the barrier of entry to immunometabolism studies and facilitate the translation of fundamental findings towards clinical applications.

Blockade of ERK signaling in KRAS-mutant pancreatic cancer increases the dependence on autophagic flux through different mechanisms and provides a rationale for combinatorial targeting with autophagy inhibitors.

Lu and colleagues delineate a pathway through which the PKM2 enzyme promotes aerobic glycolysis, known as the Warburg effect, in cancer cells. They show that EGFR-activated ERK phosphorylates PKM2, leading to its accumulation in the nucleus. Nuclear PKM2 subsequently promotes the c-Myc-dependent upregulation of genes involved in the Warburg effect, resulting in tumour growth.

New research has revealed a wealth of small molecules that target cancer-specific metabolic vulnerabilities by targeting allosteric sites. Here, a Perspective discusses how their application has provided insights into cancer metabolism and therapy.

The prodrug dimethyloxalylglycine (DMOG) is a well-known tool compound used to study hypoxia. New findings reveal that DMOG also inhibits glutamine metabolism and can be exploited to selectively kill some cancer cells, highlighting important caveats when using DMOG for hypoxia studies.

Pancreatic ductal adenocarcinoma (PDAC) cells display varying degrees of reliance on oncogenic KRAS. Here the authors show that KRAS-resistant PDAC cells maintain nucleotides synthesis through a KRAS-independent upregulation of the non-oxidative pentose phosphate pathway gene RPIA and that targeting nucleotide metabolism restore sensitivity to KRAS pathway inhibition.

The tumor microenvironment represents a stressful cellular environment. Zou and colleagues show that T_reg cells in tumors have heightened sensitivity to apoptosis, but unexpectedly this increases their suppressive potency.

Multiple sclerosis is associated with a deficiency in generation of mature oligodendroctyes; an image-based screen for oligodendrocyte differentiation inducers identified the compound benztropine, which enhances remyelination acting through muscarinic receptors and decreases clinical severity in a multiple sclerosis model system.

Using single-cell RNA sequencing, CyTOF and multiplex immunohistochemistry, Steele et al. survey the immune landscape in pancreatic cancers, adjacent tissue and blood, observing heterogeneous immune checkpoint receptor expression within patients.

Jason Locasale, Lewis Cantley, Matthew Vander Heiden and colleagues show that PHGDH is amplified in some human cancers and diverts a relatively large amount of glycolytic carbon into serine and glycine biosynthesis. They further show that PHGDH-amplified cancer cells become dependent on PHGDH for their growth, suggesting that the altered metabolic flux driven by this amplification contributes to oncogenesis.

Pancreatic adenocarcinoma cells drive autophagy in tumour microenvironment-associated stellate cells, which release alanine that is used by the cancer cells as a carbon source for a variety of metabolic processes in an otherwise nutrient-poor environment.

KRAS mutations are a driver event of pancreatic ductal adenocarcinoma; here, a subpopulation of dormant tumour cells, relying on oxidative phosphorylation for survival, is shown to be responsible for tumour relapse after treatment targeting the KRAS pathway.

Lien et al. show that oncogenic PI(3)K/Akt signalling stimulates glutathione (GSH) synthesis by activation of the transcription factor Nrf2 and regulation of GSH biosynthesis genes in breast cancer.

This protocol describes the analysis of stable isotope (¹³C and ¹⁵N) incorporation into polar metabolites in central carbon metabolic pathways using HILIC separation and selected reaction monitoring with a hybrid triple quadrupole mass spectrometer.

This Review examines the tissue-specific metabolism and associated therapeutic vulnerabilities of mutant KRAS-driven tumours, providing a comparative discussion of intrinsic metabolism, co-occurring mutations and metabolic interactions in the microenvironment in colorectal, lung and pancreatic cancer.

This Review from Jeff Rathmell and colleagues serves as a guide to immunologists on how to select the appropriate tools and techniques to interrogate metabolism in their experimental systems. The authors provide advice for avoiding common mistakes and on how best to employ metabolomics.