Latest Reviews

  • Review Article |

    Immune activating antibodies that target co-stimulatory molecules have altered the cancer therapy landscape. Here, Walker and colleagues discuss therapies — particularly those that target molecules in the same families as CTLA4 and PD1 or TNF receptor — that inhibit the immune system and are being investigated for the treatment of autoimmune diseases. They describe the future opportunities and challenges for the field, including combination approaches.

    • Natalie M. Edner
    • , Gianluca Carlesso
    • , James S. Rush
    •  & Lucy S. K. Walker
  • Review Article |

    Aberrant epigenetic processes can influence tumour immunogenicity and immune cells involved in the response to cancer. This Review highlights how epigenetic regulators can be modulated with small-molecule drugs to promote antitumour immune responses, and discusses the opportunities and challenges for developing cancer treatment regimens that combine epigenetic therapies with immunotherapies.

    • Simon J. Hogg
    • , Paul A. Beavis
    • , Mark A. Dawson
    •  & Ricky W. Johnstone
  • Review Article |

    Organs-on-chips (OoCs) could be useful at various stages of drug discovery and development, providing insight regarding human organ physiology in both normal and disease contexts, as well as accurately predicting developmental drug safety and efficacy. This Review discusses the advances that have enabled OoCs to demonstrate physiological relevance, and the challenges and opportunities that need to be tackled to tap the full potential of OoC utility for translational research.

    • Lucie A. Low
    • , Christine Mummery
    • , Brian R. Berridge
    • , Christopher P. Austin
    •  & Danilo A. Tagle
  • Perspective |

    Phase 0 approaches, including microdosing, evaluate subtherapeutic exposures to novel drugs, potentially enabling safer, cheaper and quicker first-in-human studies. Here, Burt et al. discuss the fundamentals and applications of phase 0 approaches, highlight the potential advantages of their application in drug development and address the associated limitations.

    • Tal Burt
    • , Graeme Young
    • , Wooin Lee
    • , Hiroyuki Kusuhara
    • , Oliver Langer
    • , Malcolm Rowland
    •  & Yuichi Sugiyama
  • Review Article |

    Several poly(ADP-ribose) polymerase (PARP) inhibitors have now been approved as treatments for various types of cancer. In this Review, Curtin and Szabo discuss the history of the development of PARP inhibitors and progress in their use for cancer therapy, as well as the potential for repurposing PARP inhibitors for the treatment of non-oncological diseases such as stroke.

    • Nicola J. Curtin
    •  & Csaba Szabo
  • Review Article |

    With the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. This Review analyses drugs targeting ligands that have reached clinical development in the past three decades and discusses strategic issues such as the pros and cons of different ligand-targeting therapeutic modalities.

    • Misty M. Attwood
    • , Jörgen Jonsson
    • , Mathias Rask-Andersen
    •  & Helgi B. Schiöth
  • Review Article |

    Oligonucleotide-based drugs have the potential to treat or manage a wide range of diseases. However, the widespread application of such therapies has been hampered by the difficulty in achieving efficient delivery to extrahepatic tissues. Here, Roberts et al. overview oligonucleotide-based drug platforms and assess approaches being employed to improve their delivery.

    • Thomas C. Roberts
    • , Robert Langer
    •  & Matthew J. A. Wood
  • Perspective |

    Dendritic cell vaccines have been widely investigated as a type of cancer immunotherapy, but their promise has not yet been realized. Kandalaft and colleagues propose that a prime and boost approach — primed with either standard therapies or dendritic cell vaccines and boosted with a personalized synthetic vaccine — could help fulfil the potential of such vaccines. They discuss improvements in dendritic cell vaccines that have enabled prime–boost approaches, as well as challenges for adoption.

    • Alexandre Harari
    • , Michele Graciotti
    • , Michal Bassani-Sternberg
    •  & Lana E. Kandalaft
  • Review Article |

    Radiopharmaceutical therapy is emerging as a safe and effective approach for the treatment of cancer, offering several advantages over existing therapeutic strategies. Here, Sgouros and colleagues provide an overview of the fundamental properties of radiopharmaceutical therapy, discuss agents in use and in clinical development and highlight the associated translational challenges.

    • George Sgouros
    • , Lisa Bodei
    • , Michael R. McDevitt
    •  & Jessie R. Nedrow
  • Review Article |

    Accumulating evidence indicates that impaired glucose metabolism in the brain is involved in the cause and progression of neurodegenerative disorders of ageing such as Alzheimer disease. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by rescuing, protecting or normalizing brain energetics.

    • Stephen C. Cunnane
    • , Eugenia Trushina
    • , Cecilie Morland
    • , Alessandro Prigione
    • , Gemma Casadesus
    • , Zane B. Andrews
    • , M. Flint Beal
    • , Linda H. Bergersen
    • , Roberta D. Brinton
    • , Suzanne de la Monte
    • , Anne Eckert
    • , Jenni Harvey
    • , Ross Jeggo
    • , Jack H. Jhamandas
    • , Oliver Kann
    • , Clothide Mannoury la Cour
    • , William F. Martin
    • , Gilles Mithieux
    • , Paula I. Moreira
    • , Michael P. Murphy
    • , Klaus-Armin Nave
    • , Tal Nuriel
    • , Stéphane H. R. Oliet
    • , Frédéric Saudou
    • , Mark P. Mattson
    • , Russell H. Swerdlow
    •  & Mark J. Millan
  • Review Article |

    Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) — a key mediator of cell death and inflammation — is activated in human diseases. Here, Yuan and colleagues discuss current understanding of RIPK1 biology and its association with diseases including inflammatory and autoimmune disorders, neurodegenerative diseases and sepsis. The clinical development of small-molecule RIPK1 inhibitors and associated challenges are discussed.

    • Lauren Mifflin
    • , Dimitry Ofengeim
    •  & Junying Yuan
  • Review Article |

    RAS proteins, which are frequently altered in cancer, were once considered undruggable, but compounds targeting some mutant RAS proteins have recently demonstrated clinical efficacy. In this Review, Malek and colleagues explore how these and other drugs that target RAS or associated pathways might be used effectively, particularly in combinations, and discuss other RAS-targeted therapies in the pipeline.

    • Amanda R. Moore
    • , Scott C. Rosenberg
    • , Frank McCormick
    •  & Shiva Malek
  • Review Article |

    Several biological phenomena alter the ageing process. This Review discusses the most promising agents to slow ageing, separating them into two tiers based on their efficacy and evidence. The potential use of some interventions in clinical trials to expand overall healthspan as well as how those interventions could be assessed are also discussed.

    • Linda Partridge
    • , Matias Fuentealba
    •  & Brian K. Kennedy
  • Review Article |

    This Review highlights the challenges of using mouse models to advance drug discovery in Alzheimer disease, discussing the emerging opportunities to optimize disease modelling and alternative preclinical research systems to test therapeutic approaches in this highly prevalent disease.

    • Kimberly Scearce-Levie
    • , Pascal E. Sanchez
    •  & Joseph W. Lewcock
  • Review Article |

    Primary stem cells have long been used therapeutically for applications such as bone marrow transplantation. This Review discusses how cell-engineering approaches are enabling the development of next-generation stem cell therapies with improved function, specificity and responsiveness, thereby expanding their applications into areas such as delivering drugs and oncolytic viruses to tumours and promoting tissue repair in various diseases.

    • Erin A. Kimbrel
    •  & Robert Lanza
  • Review Article |

    Many G protein-coupled receptors (GPCRs) have endogenous peptide agonists, and modifying the sequence of these peptides has led to some successful therapeutics. In this Review, Davenport and colleagues discuss strategies to generate effective GPCR-targeted peptide therapeutics by introducing chemical novelty, extending plasma half-life, improving a therapeutic’s drug-like properties or generating biased ligands. These approaches could overcome some of the challenges in developing peptide therapeutics.

    • Anthony P. Davenport
    • , Conor C. G. Scully
    • , Chris de Graaf
    • , Alastair J. H. Brown
    •  & Janet J. Maguire
  • Review Article |

    Communities of structural, metabolic and signalling proteins modulate downstream effects that result in differences in efficacy, adverse effects and resistance to therapy. This Review discusses how proteomic technologies are expanding our understanding of protein communities and of their responses to therapeutics.

    • Hanna G. Budayeva
    •  & Donald S. Kirkpatrick
  • Review Article |

    Existing antiplatelet and anticoagulant agents for the prevention and treatment of thrombosis are associated with bleeding risk. Here, Mackman and colleagues provide an overview of haemostasis and thrombosis and assess the advantages and limitations of existing antithrombotics. The emerging antithrombotic targets and agents in development as well as the associated challenges are discussed.

    • Nigel Mackman
    • , Wolfgang Bergmeier
    • , George A. Stouffer
    •  & Jeffrey I. Weitz
  • Review Article |

    Naturally occurring cationic host defence peptides, also known as antimicrobial peptides, can control infections by their direct microbicidal properties and by modulating the host’s immune responses. In addition, certain cationic host defence peptides can resolve harmful inflammation. Here, Mookherjee et al. assess the emerging potential to therapeutically harness these peptides to treat infectious diseases, chronic inflammatory disorders and wound healing, highlighting current preclinical studies and clinical trials.

    • Neeloffer Mookherjee
    • , Marilyn A. Anderson
    • , Henk P. Haagsman
    •  & Donald J. Davidson
  • Review Article |

    Current seasonal influenza vaccines lack efficacy against drifted or pandemic virus strains, and the development of novel vaccines that elicit broader immunity represents a public health priority. Here, Nabel and colleagues discuss approaches to improve vaccine efficacy which harness new insights from influenza antigen structure and human immunity, highlighting major targets, vaccines in development and ongoing challenges.

    • Chih-Jen Wei
    • , Michelle C. Crank
    • , John Shiver
    • , Barney S. Graham
    • , John R. Mascola
    •  & Gary J. Nabel
  • Review Article |

    Neutrophils play diverse roles in various disease processes, including infection, pulmonary diseases, autoimmune and inflammatory disorders, cardiovascular diseases and cancer. Here, Mócsai and colleagues provide an overview of the biological and pathological functions of neutrophils, assessing emerging strategies to therapeutically target neutrophils and agents currently under investigation.

    • Tamás Németh
    • , Markus Sperandio
    •  & Attila Mócsai
  • Review Article |

    Natural killer (NK) cells have a primordial role in tumour immunosurveillance. Given their potent antitumour activity, therapeutic manipulation of NK cells provides an attractive strategy for cancer treatment. This Review discusses new approaches to activate NK cells, increase their proliferation in vivo and increase their capacity to recognize tumour cells.

    • Noriko Shimasaki
    • , Amit Jain
    •  & Dario Campana
  • Review Article |

    The use of allogeneic chimeric antigen receptor T cells from donors has many potential advantages over autologous approaches, such as immediate availability, standardization and the possibility of redosing or combination. This Review analyses the different sources of T cells and technological approaches to produce optimal allogeneic chimeric antigen receptor T cells with limited potential for graft-versus-host disease and increased persistence.

    • S. Depil
    • , P. Duchateau
    • , S. A. Grupp
    • , G. Mufti
    •  & L. Poirot
  • Perspective |

    Oral delivery of peptide therapeutics could have benefits for treatment adherence, but it faces barriers related to the structural organization and physiological function of the gastrointestinal tract. This article highlights strategies to overcome these barriers and discusses experience with oral peptides that have reached clinical trials, including the recent landmark approval of an oral formulation of semaglutide for the treatment of type 2 diabetes.

    • Daniel J. Drucker
  • Review Article |

    Most rare diseases still lack approved treatments. This article analyses the main therapeutic modalities available to researchers interested in translating advances in the scientific understanding of rare diseases into therapies, highlights progress so far and discusses overarching issues in drug development for rare diseases.

    • Erik Tambuyzer
    • , Benjamin Vandendriessche
    • , Christopher P. Austin
    • , Philip J. Brooks
    • , Kristina Larsson
    • , Katherine I. Miller Needleman
    • , James Valentine
    • , Kay Davies
    • , Stephen C. Groft
    • , Robert Preti
    • , Tudor I. Oprea
    •  & Marco Prunotto
  • Perspective |

    Artificial intelligence (AI) tools are increasingly being applied in drug discovery. This article presents the views of a group of international experts on the ‘grand challenges’ in small-molecule drug discovery with AI, including obtaining appropriate data sets, generating new hypotheses, optimizing in a multi-objective manner, reducing cycle times and changing the research culture.

    • Petra Schneider
    • , W. Patrick Walters
    • , Alleyn T. Plowright
    • , Norman Sieroka
    • , Jennifer Listgarten
    • , Robert A. Goodnow Jr.
    • , Jasmin Fisher
    • , Johanna M. Jansen
    • , José S. Duca
    • , Thomas S. Rush
    • , Matthias Zentgraf
    • , John Edward Hill
    • , Elizabeth Krutoholow
    • , Matthias Kohler
    • , Jeff Blaney
    • , Kimito Funatsu
    • , Chris Luebkemann
    •  & Gisbert Schneider
  • Perspective |

    Current preclinical models poorly predict the potential of a new drug candidate to cause drug-induced liver injury (DILI) in humans. Here, Park and colleagues discuss current understanding of the mechanisms mediating DILI and, through an academic–industry collaboration, propose a roadmap for the development of predictive preclinical models of human DILI.

    • Richard J. Weaver
    • , Eric A. Blomme
    • , Amy E. Chadwick
    • , Ian M. Copple
    • , Helga H. J. Gerets
    • , Christopher E. Goldring
    • , Andre Guillouzo
    • , Philip G. Hewitt
    • , Magnus Ingelman-Sundberg
    • , Klaus Gjervig Jensen
    • , Satu Juhila
    • , Ursula Klingmüller
    • , Gilles Labbe
    • , Michael J. Liguori
    • , Cerys A. Lovatt
    • , Paul Morgan
    • , Dean J. Naisbitt
    • , Raymond H. H. Pieters
    • , Jan Snoeys
    • , Bob van de Water
    • , Dominic P. Williams
    •  & B. Kevin Park
  • Review Article |

    Genomic screenings have enabled the discovery of synthetic lethal partners as potential drug targets in cancer. This Review discusses how the genetic concept of synthetic lethality paired with CRISPR-based functional genomic screening can be applied to identify additional synthetic lethal pairs as new and druggable cancer targets.

    • Alan Huang
    • , Levi A. Garraway
    • , Alan Ashworth
    •  & Barbara Weber
  • Perspective |

    Small molecules that induce targeted protein degradation by the ubiquitin–proteasome system, such as proteolysis-targeting chimeras (PROTACs), are attracting great interest as a new therapeutic modality. This Perspective discusses opportunities and challenges for expanding the applicability of targeted protein degradation, with a focus on the large family of E3 ubiquitin ligases that have a key role in the process.

    • Matthieu Schapira
    • , Matthew F. Calabrese
    • , Alex N. Bullock
    •  & Craig M. Crews
  • Review Article |

    Cell plasticity has emerged as a mode of targeted therapy evasion in various cancers. This Review discusses the different mechanisms that drive tumour cell plasticity and the potential therapeutic strategies to target them in order to achieve more durable clinical responses.

    • Soufiane Boumahdi
    •  & Frederic J. de Sauvage
  • Review Article |

    Precursor mRNA processing, which includes the removal of introns by splicing and the formation of 3′ ends by cleavage and polyadenylation, is frequently altered in tumours. This Review describes small molecules and oligonucleotides that modulate the spliceosome and are now in clinical trials for the treatment of cancer.

    • Joana Desterro
    • , Pedro Bak-Gordon
    •  & Maria Carmo-Fonseca
  • Review Article |

    Nucleic acid sensors (NASs) are essential for the preservation of cellular and organismal homeostasis, with dysregulated NAS signalling contributing to the pathology of a variety of conditions, including infectious diseases, autoimmune disorders and malignancy. Here, Galluzzi and colleagues discuss recent progress in the development of therapeutic NAS modulators and highlight obstacles faced in their clinical development.

    • Claire Vanpouille-Box
    • , Jules A. Hoffmann
    •  & Lorenzo Galluzzi
  • Review Article |

    Fibrosis features in numerous chronic diseases, such as non-alcoholic steatohepatitis and heart failure, and no existing therapies can prevent or reverse this abnormal deposition of extracellular matrix, which leads to organ dysfunction. Here, Liu and colleagues describe how this energy-intensive process could be targeted by therapies that interfere with metabolism, including the metabolic implications of drugs directed at transforming growth factor-β and the deposition of extracellular matrix.

    • Xiao Zhao
    • , Jennifer Yin Yee Kwan
    • , Kenneth Yip
    • , Peter P. Liu
    •  & Fei-Fei Liu
  • Review Article |

    Our increased understanding of how regulatory T cells suppress immune responses has led to their use in early-phase clinical trials for inflammatory disorders, with promising results. This Review describes the key advances and prospects in designing and implementing regulatory T cells as multifaceted, adaptable smart therapeutics in autoimmunity and transplantation.

    • Leonardo M. R. Ferreira
    • , Yannick D. Muller
    • , Jeffrey A. Bluestone
    •  & Qizhi Tang
  • Author Correction |

    • Derek C. Angus
    • , Brian M. Alexander
    • , Scott Berry
    • , Meredith Buxton
    • , Roger Lewis
    • , Melissa Paoloni
    • , Steven A. R. Webb
    • , Steven Arnold
    • , Anna Barker
    • , Donald A. Berry
    • , Marc J. M. Bonten
    • , Mary Brophy
    • , Christopher Butler
    • , Timothy F. Cloughesy
    • , Lennie P. G. Derde
    • , Laura J. Esserman
    • , Ryan Ferguson
    • , Louis Fiore
    • , Sarah C. Gaffey
    • , J. Michael Gaziano
    • , Kathy Giusti
    • , Herman Goossens
    • , Stephane Heritier
    • , Bradley Hyman
    • , Michael Krams
    • , Kay Larholt
    • , Lisa M. LaVange
    • , Philip Lavori
    • , Andrew W. Lo
    • , Alex John London
    • , Victoria Manax
    • , Colin McArthur
    • , Genevieve O’Neill
    • , Giovanni Parmigiani
    • , Jane Perlmutter
    • , Elizabeth A. Petzold
    • , Craig Ritchie
    • , Kathryn M. Rowan
    • , Christopher W. Seymour
    • , Nathan I. Shapiro
    • , Diane M. Simeone
    • , Bradley Smith
    • , Bradley Spellberg
    • , Ariel Dora Stern
    • , Lorenzo Trippa
    • , Mark Trusheim
    • , Kert Viele
    • , Patrick Y. Wen
    •  & Janet Woodcock
  • Review Article |

    γδT cells display potent cytotoxicity towards a large array of haematological and solid tumours while preserving normal tissues. In this Review, Sebestyen et al. analyse the tumour specificity mechanisms of γδT cells and the challenges and opportunities for the use of such cells and their receptors in cancer immunotherapy.

    • Zsolt Sebestyen
    • , Immo Prinz
    • , Julie Déchanet-Merville
    • , Bruno Silva-Santos
    •  & Jurgen Kuball
  • Review Article |

    Defective lysosomal function has been implicated in diseases ranging from rare lysosomal storage disorders to more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. Here, Muller and colleagues provide an overview of the physiological and pathological roles of lysosomes and assess the progress and opportunities for therapeutically targeting lysosomal proteins and processes.

    • Srinivasa Reddy Bonam
    • , Fengjuan Wang
    •  & Sylviane Muller
  • Perspective |

    Adaptive platform trials, which can study multiple therapeutic interventions in a disease in a perpetual manner, offer the potential to improve the efficiency of drug development. This article reviews common features and issues that arise with such trials, and puts forward recommendations to promote best practices in their design, conduct, oversight and reporting.

    • Derek C. Angus
    • , Brian M. Alexander
    • , Scott Berry
    • , Meredith Buxton
    • , Roger Lewis
    • , Melissa Paoloni
    • , Steven A. R. Webb
    • , Steven Arnold
    • , Anna Barker
    • , Donald A. Berry
    • , Marc J. M. Bonten
    • , Mary Brophy
    • , Christopher Butler
    • , Timothy F. Cloughesy
    • , Lennie P. G. Derde
    • , Laura J. Esserman
    • , Ryan Ferguson
    • , Louis Fiore
    • , Sarah C. Gaffey
    • , J. Michael Gaziano
    • , Kathy Giusti
    • , Herman Goossens
    • , Stephane Heritier
    • , Bradley Hyman
    • , Michael Krams
    • , Kay Larholt
    • , Lisa M. LaVange
    • , Philip Lavori
    • , Andrew W. Lo
    • , Alex John London
    • , Victoria Manax
    • , Colin McArthur
    • , Genevieve O’Neill
    • , Giovanni Parmigiani
    • , Jane Perlmutter
    • , Elizabeth A. Petzold
    • , Craig Ritchie
    • , Kathryn M. Rowan
    • , Christopher W. Seymour
    • , Nathan I. Shapiro
    • , Diane M. Simeone
    • , Bradley Smith
    • , Bradley Spellberg
    • , Ariel Dora Stern
    • , Lorenzo Trippa
    • , Mark Trusheim
    • , Kert Viele
    • , Patrick Y. Wen
    •  & Janet Woodcock
  • Perspective |

    Adhesion G protein-coupled receptors (aGPCRs) have been linked to multiple diseases, but no therapeutics targeting this GPCR family are yet in clinical trials, in part because a lack of understanding of the atypical features of aGPCRs has hampered the development of molecules targeting them. In this Perspective, Bassilana and colleagues discuss how recent advances in aGPCR biology could provide the basis for a framework to approach the unique challenges of drug discovery programmes targeting these receptors.

    • Frederic Bassilana
    • , Mark Nash
    •  & Marie-Gabrielle Ludwig
  • Review Article |

    Drug development for treatment of hepatitis B virus infection has trailed behind that for infection with the related hepatitis C virus, but encouraging progress has been made in recent years. Fanning and colleagues review advances in hepatitis B therapies and challenges for their development, including antiviral and immune-boosting strategies that could be part of combination strategies to achieve functional cure.

    • Gregory C. Fanning
    • , Fabien Zoulim
    • , Jinlin Hou
    •  & Antonio Bertoletti
  • Review Article |

    The pathophysiological complexity of progressive multiple sclerosis (MS) challenges the development of effective treatments, despite the substantial unmet clinical need. In this Review, Faissner, Yong and colleagues highlight the need for therapies that target inflammation, neurodegeneration and remyelination, which will likely be needed in combination. The setbacks encountered so far and future challenges are also discussed.

    • Simon Faissner
    • , Jason R. Plemel
    • , Ralf Gold
    •  & V. Wee Yong
  • Review Article |

    Cyclic nucleotide phosphodiesterases (PDEs) have roles in numerous biological processes and their dysfunction has been associated with various diseases including those affecting the nervous system, the cardiovascular system, fertility, immunity, cancer and metabolism. Here, Kelly and colleagues assess the current status of therapeutic PDE inhibitors, and highlight emerging novel strategies to therapeutically target PDE function.

    • George S. Baillie
    • , Gonzalo S. Tejeda
    •  & Michy P. Kelly
  • Review Article |

    Metabolic reprogramming alters immune cell activation, differentiation and function. Powell and colleagues discuss how to specifically modulate the activity of immune cells by altering their metabolism, suggesting a model of ‘cellular selectivity based on demand’, and highlight the opportunities to therapeutically target immunometabolism in cancer and autoimmune disorders.

    • Chirag H. Patel
    • , Robert D. Leone
    • , Maureen R. Horton
    •  & Jonathan D. Powell