Reviews & Analysis

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.

In this Review, Dey and colleagues discuss the key findings from studies of Hippo pathway signalling across biological processes and diseases, and discuss new strategies and therapeutic implications of targeting this pathway.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.