Endothelial cells (ECs) are highly glycolytic, but whether they generate glycolytic intermediates via gluconeogenesis (GNG) in glucose-deprived conditions remains unknown. Here, we report that glucose-deprived ECs upregulate the GNG enzyme PCK2 and rely on a PCK2-dependent truncated GNG, whereby lactate and glutamine are used for the synthesis of lower glycolytic intermediates that enter the serine and glycerophospholipid biosynthesis pathways, which can play key roles in redox homeostasis and phospholipid synthesis, respectively. Unexpectedly, however, even in normal glucose conditions, and independent of its enzymatic activity, PCK2 silencing perturbs proteostasis, beyond its traditional GNG role. Indeed, PCK2-silenced ECs have an impaired unfolded protein response, leading to accumulation of misfolded proteins, which due to defective proteasomes and impaired autophagy, results in the accumulation of protein aggregates in lysosomes and EC demise. Ultimately, loss of PCK2 in ECs impaired vessel sprouting. This study identifies a role for PCK2 in proteostasis beyond GNG. This study reports a unexpected role in endothelial cells (ECs) for PCK2 in proteostasis, independent of its gluconeogenic activity. Perturbation of this role likely contributed to the angiogenic defects observed in ECs with reduced PCK2 levels.

Somasundara, Moss, Feigman et al. show that γδ natural killer T-like (NKT) cells expand during the late stages of pregnancy in mice because of changes in mammary epithelial cell surface protein expression, which was associated with suppressed mammary oncogenesis induced by BRCA1 loss or MYC-overexpression.

ir et al. show that tumour-associated high endothelial venues (TA-HEVs) in tumour-bearing mice are points of entry for lymphocytes, and increasing TA-HEVs frequency and maturation improves immune checkpoint blockade.

North, Benbarche et al. engineered synthetic introns that were spliced specifically in cancer cells expressing the mutant spliceosome factor SF3B1. This led to expression of herpes simplex virus-thymidine kinase and vulnerability of cancer cells to treatment with the antiviral drug ganciclovir.

Torrino et al. report that extracellular matrix stiffening stabilizes microtubules by glutaminolysis-dependent microtubule glutamylation, thereby promoting breast cancer progression.

Bartok, Pataskar, Nagel et al. show that long-term interferon γ-induced tryptophan degradation interferes with mRNA translation in melanoma. They reveal a mechanism by which indoleamine 2,3-dioxygenase 1 and amino acid starvation-dependent ribosomal frameshifting leads to immunogenic aberrant peptide presentation.

Biswas et al. show that B cell infiltration in ovarian cancer leads to humoral immune responses dominated by polyclonal IgA, which mark ovarian cancer cells to be removed by myeloid cells, and also sensitize cancer cells to T cell-mediated cytolysis thereby controlling tumour growth.

Liu et al. show that glycogen accumulates in pre-malignant liver cells by undergoing liquid–liquid phase separation and, by sequestering Hippo kinases MST1 and MST2, promotes YAP-driven tumorigenesis.

Wang et al. showed that monoamine-oxidase A, a regulator of neuronal activity, functions as a negative feedback regulator of T cell activity in tumours.

Canale et al. engineered the bacterial strain Escherichia coli Nissle 1917 to recycle ammonia into arginine, and showed synergistic responses with anti-programmed cell death 1 ligand 1 therapy in tumour-bearing mice when injected intratumourally or given systemically.

Bertocchi et al. show that tumour-resident bacteria in colorectal cancer disseminate to the liver via an impaired gut vascular barrier and promote the liver pre-metastatic niche.

Casanova-Acebes et al. show that tissue-resident macrophages provide a unique niche for tumour cells in the lung to promote invasiveness and regulatory T cell-mediated immune suppression.

Using a rapid mass-spectrometry based approach to analyse aerosol released during surgical cauterization of tumour tissue, Koundouros et al. derived metabolic signatures associated with the tumour genotype. Based on these signatures, they identified a new mechanism by which oncogenic PI3K signalling promotes tumour growth.

Jansen et al. show in patients with cancer that intratumoural stem-like CD8+ T cells reside in antigen-presenting cell (APC) niches in the tumour and give rise to terminally differentiated T cells.

Chung et al. studied drivers of obesity-associated pancreatic ductal adenocarcinoma in a leptin-deficient mouse model and identified the hormone cholecystokinin, upregulated in islet beta cells in the context of obesity, to be promoting pancreatic tumorigenesis.

Hoekstra et al. and Thibaut et al., both reporting in Nature Cancer , show that interferon-γ secreted by tumour-reactive T cells diffuses into the tumour microenvironment and acts on remote tumour cells to modify tumour behaviour.

Ostendorf et al. show that germline variants of human APOE play a role in melanoma that is opposite to that in Alzheimer disease, with APOE4 carrier status being associated with reduced melanoma growth in mice and improved outcome in patients with advanced melanoma.

Angiogenesis, the formation of new blood vessels by endothelial cells, is a finely tuned process relying on the balance between promoting and repressing signalling pathways. Among these, Notch signalling is critical in ensuring appropriate response of endothelial cells to pro-angiogenic stimuli. However, the downstream targets and pathways effected by Delta-like 4 (DLL4)/Notch signalling and their subsequent contribution to angiogenesis are not fully understood. We found that the Rho GTPase, RHOQ, is induced by DLL4 signalling and that silencing RHOQ results in abnormal sprouting and blood vessel formation both in vitro and in vivo. Loss of RHOQ greatly decreased the level of Notch signalling, conversely overexpression of RHOQ promoted Notch signalling. We describe a new feed-forward mechanism regulating DLL4/Notch signalling, whereby RHOQ is induced by DLL4/Notch and is essential for the NICD nuclear translocation. In the absence of RHOQ, Notch1 becomes targeted for degradation in the autophagy pathway and NICD is sequestered from the nucleus and targeted for degradation in lysosomes.

Strickley, Messerschmidt et al. show that beta human papilloma virus (β-HPV) infection itself is not causal in cutaneous squamous cell carcinoma (SCC) development in the context of immunosuppression — instead, the loss of β-HPV-mediated T cell immunity promotes SCC.

Banh et al. show that peripheral axons of sensory nerves release serine into the tumour microenvironment, which can support the growth of extracellular serine-dependent pancreatic ductal adenocarcinoma by promoting mRNA translation.