TY - JOUR AB - The depletion or accumulation of metabolites in the tumour microenvironment is one of the hallmarks of cancer, but targeting cancer cell metabolism therapeutically must also take into account the impact on metabolic pathways in immune cells. As we understand more about immunometabolism, opportunities arise for synergies between agents that modulate metabolism and immunotherapy. In this Review, we discuss the pivotal role of metabolic pathways in both cancer and immune cells in shaping the tumour microenvironment. We survey major anabolic and catabolic pathways and discuss how metabolic modulators and dietary nutrients can improve the anticancer immune response and overcome drug resistance mechanisms. Agents in the clinic include inhibitors of the adenosine and tryptophan pathways, and we discuss opportunities and challenges for successful drug development in the context of immune checkpoint blockade and chimeric antigen receptor (CAR)-T cell therapies. AU - Trefny, M.P.* AU - Kroemer, G.* AU - Zitvogel, L.* AU - Kobold, S. C1 - 75034 C2 - 57727 CY - Heidelberger Platz 3, Berlin, 14197, Germany TI - Metabolites as agents and targets for cancer immunotherapy. JO - Nat. Rev. Drug Discov. PB - Nature Portfolio PY - 2025 SN - 1474-1776 ER - TY - JOUR AB - Cell death is critical for the development and homeostasis of almost all multicellular organisms. Moreover, its dysregulation leads to diverse disease states. Historically, apoptosis was thought to be the major regulated cell death pathway, whereas necrosis was considered to be an unregulated form of cell death. However, research in recent decades has uncovered several forms of regulated necrosis that are implicated in degenerative diseases, inflammatory conditions and cancer. The growing insight into these regulated, non-apoptotic cell death pathways has opened new avenues for therapeutic targeting. Here, we describe the regulatory pathways of necroptosis, pyroptosis, parthanatos, ferroptosis, cuproptosis, lysozincrosis and disulfidptosis. We discuss small-molecule inhibitors of the pathways and prospects for future drug discovery. Together, the complex mechanisms governing these pathways offer strategies to develop therapeutics that control non-apoptotic cell death. AU - Hadian, K. AU - Stockwell, B.R.* C1 - 68023 C2 - 54501 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 723-742 TI - The therapeutic potential of targeting regulated non-apoptotic cell death. JO - Nat. Rev. Drug Discov. VL - 22 IS - 9 PB - Nature Portfolio PY - 2023 SN - 1474-1776 ER - TY - JOUR AB - Enormous progress has been made in the last half-century in the management of diseases closely integrated with excess body weight, such as hypertension, adult-onset diabetes and elevated cholesterol. However, the treatment of obesity itself has proven largely resistant to therapy, with anti-obesity medications (AOMs) often delivering insufficient efficacy and dubious safety. Here, we provide an overview of the history of AOM development, focusing on lessons learned and ongoing obstacles. Recent advances, including increased understanding of the molecular gut–brain communication, are inspiring the pursuit of next-generation AOMs that appear capable of safely achieving sizeable and sustained body weight loss. AU - Müller, T.D. AU - Blüher, M. AU - Tschöp, M.H. AU - DiMarchi, R.D.* C1 - 63612 C2 - 51563 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 201-223 TI - Anti-obesity drug discovery: Advances and challenges. JO - Nat. Rev. Drug Discov. VL - 21 IS - 3 PB - Nature Portfolio PY - 2022 SN - 1474-1776 ER - TY - JOUR AB - Diabetes mellitus is a metabolic disorder that affects more than 460 million people worldwide. Type 1 diabetes (T1D) is caused by autoimmune destruction of β-cells, whereas type 2 diabetes (T2D) is caused by a hostile metabolic environment that leads to β-cell exhaustion and dysfunction. Currently, first-line medications treat the symptomatic insulin resistance and hyperglycaemia, but do not prevent the progressive decline of β-cell mass and function. Thus, advanced therapies need to be developed that either protect or regenerate endogenous β-cell mass early in disease progression or replace lost β-cells with stem cell-derived β-like cells or engineered islet-like clusters. In this Review, we discuss the state of the art of stem cell differentiation and islet engineering, reflect on current and future challenges in the area and highlight the potential for cell replacement therapies, disease modelling and drug development using these cells. These efforts in stem cell and regenerative medicine will lay the foundations for future biomedical breakthroughs and potentially curative treatments for diabetes. AU - Siehler, J. AU - Blöchinger, A. AU - Meier, M. AU - Lickert, H. C1 - 62799 C2 - 51069 CY - Heidelberger Platz 3, Berlin, 14197, Germany SP - 920–940 TI - Engineering islets from stem cells for advanced therapies of diabetes. JO - Nat. Rev. Drug Discov. VL - 20 PB - Nature Portfolio PY - 2021 SN - 1474-1776 ER - TY - JOUR AB - The discovery of regulated cell death presents tantalizing possibilities for gaining control over the life-death decisions made by cells in disease. Although apoptosis has been the focus of drug discovery for many years, recent research has identified regulatory mechanisms and signalling pathways for previously unrecognized, regulated necrotic cell death routines. Distinct critical nodes have been characterized for some of these alternative cell death routines, whereas other cell death routines are just beginning to be unravelled. In this Review, we describe forms of regulated necrotic cell death, including necroptosis, the emerging cell death modality of ferroptosis (and the related oxytosis) and the less well comprehended parthanatos and cyclophilin D-mediated necrosis. We focus on small molecules, proteins and pathways that can induce and inhibit these non-apoptotic forms of cell death, and discuss strategies for translating this understanding into new therapeutics for certain disease contexts. AU - Conrad, M. AU - Friedmann Angeli, J.P.F. AU - Vandenabeele, P.* AU - Stockwell, B.R.* C1 - 47707 C2 - 39552 CY - London SP - 348-366 TI - Regulated necrosis: Disease relevance and therapeutic opportunities. JO - Nat. Rev. Drug Discov. VL - 15 IS - 5 PB - Nature Publishing Group PY - 2016 SN - 1474-1776 ER - TY - JOUR AB - Forkhead box P3 (FOXP3)-expressing regulatory T (T-Reg) cells have a pivotal role in the regulation of immune responses and in the maintenance of immunological self-tolerance. These cells have emerged as attractive targets for strategies that allow the steering of immune responses in desired directions-arming the immune system to destroy infected cells and cancer cells or downregulating it to limit tissue destruction in autoimmunity. Efforts to understand the generation, activation and function of T-Reg cells should permit the development of therapeutics for reprogramming the immune system. In this Review, we discuss insights into the generation of T-Reg cells, their involvement in disease and the molecular basis of the dominant tolerance exerted by FOXP3(+) T-Reg cells that could permit their safe and specific manipulation in humans. AU - von Boehmer, H.* AU - Daniel, C. C1 - 22400 C2 - 30890 SP - 51-63 TI - Therapeutic opportunities for manipulating TReg cells in autoimmunity and cancer. JO - Nat. Rev. Drug Discov. VL - 12 IS - 1 PB - Nature Publishing Group PY - 2013 SN - 1474-1776 ER -