strate that in naïve CD4 T cells from older individuals, mTORC1 activation instead occurs at late endosomes and depends on the amino acid transporter SLC7A5. Late endosomal mTORC1 impairs T cell lysosomal function, reducing the degradation of PD-1 and proliferative responses. Silencing VPS39, a gene that promotes late endosome formation, was able to increase the proliferation of aged human T cells and memory responses of lysosome-defective T cells in a mouse viral infection model, demonstrating that targeting late endosomal mTORC1 activity may improve T cell function. —CO Sci. Immunol. 6, eabg0791 (2021).

Coronavirus When viruses enter cells or cause their lysis, lipids can be released. These lipids can be modified to become bioactive and have roles in modulating antiviral immune responses, especially inflammation. In a Perspective, Theken and FitzGerald discuss the possible roles of bioactive lipids in immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Bioactive lipids are the targets of multiple drugs, and the authors also discuss whether they can be repurposed to treat COVID-19. Science , this issue p. [237][1] [1]: /lookup/doi/10.1126/science.abf3192

Cancer Numerous cancer-specific alterations in metabolism have been identified but have not yet resulted in an effective anti cancer therapeutic. In a Review, Faubert et al. discuss how metabolism changes as cancer develops from a small, premalignant lesion to an aggressive primary tumor and then metastasizes. Metabolic vulnerabilities likely change with cancer progression, making the identification of general cancer-associated metabolic features difficult. The authors propose that a more targeted approach to tissues and vulnerabilities identified in patients may be more effective. Science , this issue p. [eaaw5473][1] [1]: /lookup/doi/10.1126/science.aaw5473

Systems Biology Single-cell DNA and RNA sequencing can describe numerous aspects of cell state, but such techniques cannot assess the functional effectors of cells: proteins. In a Perspective, Slavlov discusses the advances in single-cell mass spectrometry techniques that allow protein profiling, including characterization of protein modifications and potentially complex composition and subcellular localization. Although there are limitations to this emerging technology, single-cell proteomics may add to the characterization of cellular components and provide functional information about signaling networks in homeostasis and disease. Science , this issue p. [512][1] [1]: /lookup/doi/10.1126/science.aaz6695

Biotechnology Genetically modified crops have supporters and opponents, but how can these views be reconciled to improve food security? This problem is particularly acute for middle-income countries that need to export crops to maintain their economy as well as provide for their expanding population. In a Perspective, Zaidi et al. discuss the promise of new plant breeding technologies to edit endogenous genes in crop plants. These innovations will ideally improve food security and avoid barriers to use and implementation that face traditional genetically modified crops. Science , this issue p. [1390][1] [1]: /lookup/volpage/363/1390?iss=6434

Signaling Sphingosine 1-phosphate (S1P) is an important circulating lipid mediator that is derived from the metabolism of cell membranes. Its diverse homeostatic roles, particularly in immunology and vascular biology, can go awry in numerous diseases, including multiple sclerosis, cardiovascular diseases, and fibrosis. The centrality of S1P signaling has led to the development of several drugs, including two approved for treatment of multiple sclerosis. In a Review, Cartier and Hla discuss the current understanding of how one mediator can carry out so many signaling roles in different tissues, how these become dysregulated in disease, and efforts in drug development to target S1P signaling. Science , this issue p. [eaar5551][1] [1]: /lookup/doi/10.1126/science.aar5551

CancerThe RAS signaling pathway controls cell survival and proliferation and is a possible target for cancer treatment. However, therapeutically targeting RAS is challenging. In a Perspective, Bivona discusses recent studies that identify upstream targets, the inhibition of which could suppress RAS signaling in cancer. Certain cancer-associated RAS pathway alterations leave RAS sensitive to regulation by signaling adaptors. Preclinical studies suggest that this regulation can be targeted to prevent RAS signaling and thus tumor progression.Science , this issue p. [1280][1] [1]: /lookup/doi/10.1126/science.aav6703

Immunology Accumulating evidence suggests that a nonclassical antigen presentation pathway, mediated by human leukocyte antigen–E (HLA-E), has an important role in regulating innate and adaptive immune responses to infections and cancer. In a Perspective, Ottenhoff and Joosten discuss the dichotomous role of HLA-E in suppressing immune responses (through an immune checkpoint), as well as in activating unconventional T cells. This nonclassical pathway has the potential to be manipulated to prevent infectious disease through vaccination and to treat cancer through immunotherapy. Science , this issue p. [302][1] [1]: /lookup/doi/10.1126/science.aay7079

Two papers demonstrate that early disseminated cancer cells (DCCs) from HER2 + breast cancer are more likely to seed metastasis than those from established tumours.

Cancer Immunotherapy Nivolumab, an immunotherapy drug, has shown unprecedented success at treating patients with certain types of advanced cancer. The U.S. Food and Drug Administration approvals for nivolumab, and other drugs like it, are for patients with advanced cancer that has progressed or relapsed while on chemotherapy. Carbone et al. tested whether nivolumab could be used as a first-line therapy (before chemotherapy) in lung cancer patients that express the nivolumab target, PD1, and unexpectedly found that the drug was not better than chemotherapy. Compared with chemotherapy, nivolumab did not extend the time before the disease progressed, nor did it improve overall survival. These results suggest that pretreatment with chemotherapy may influence the response to nivolumab. N. Engl. J. Med. 376 , 2415 (2017).

paper in Science by Tomasetti, Li and Vogelstein develops their 'bad luck' model further and explores how different sources of DNA mutation influence different cancer types.

report in Science Translational Medicine provides the first example of using universal engineered chimeric antigen receptor (CAR) T cells from human leukocyte antigen (HLA)-mismatched donors.

Two papers assess the role of glucose in lung cancer metabolism in vivo .