Nature Reviews Drug Discovery最新文献

Regulatory T (T_reg) cells are a suppressive subset of CD4⁺ T cells that maintain immune homeostasis and restrain inflammation. Three decades after their discovery, the promise of strategies to harness T_reg cells for therapy has never been stronger. Multiple clinical trials seeking to enhance endogenous T_reg cells or deliver them as a cell-based therapy have been performed and hint at signs of success, as well as to important limitations and unanswered questions. Strategies to deplete T_reg cells in cancer are also in active clinical testing. Furthermore, multi-dimensional methods to interrogate the biology of T_reg cells are leading to a refined understanding of T_reg cell biology and new approaches to harness tissue-specific functions for therapy. A new generation of T_reg cell clinical trials is now being fuelled by advances in nanomedicine and synthetic biology, seeking more precise ways to tailor T_reg cell function. This Review will discuss recent advances in our understanding of human T_reg cell biology, with a focus on mechanisms of action and strategies to assess outcomes of T_reg cell-targeted therapies. It highlights results from recent clinical trials aiming to enhance or inhibit T_reg cell activity in a variety of diseases, including allergy, transplantation, autoimmunity and cancer, and discusses ongoing strategies to refine these approaches.

The importance of metabolic pathways in regulating immune responses is now well established, and a mapping of the bioenergetic metabolism of different immune cell types is under way. CD8 T cells and natural killer (NK) cells contribute to cancer immunosurveillance through their cytotoxic functions and secretion of cytokines and chemokines, complementing each other in target recognition mechanisms. Several immunotherapies leverage these cell types by either stimulating their activity or redirecting their specificity against tumour cells. However, the anticancer activity of CD8 T cells and NK cells is rapidly diminished in the tumour microenvironment, closely linked to a decline in their metabolic capacities. Various strategies have been developed to restore cancer immunosurveillance, including targeting bioenergetic metabolism or genetic engineering. This Review provides an overview of metabolic dysfunction in CD8 T cells and NK cells within the tumour microenvironment, highlighting current therapies aiming to overcome these issues.

Improved understanding of cancer immunology has gradually brought increasing attention towards cancer-preventive vaccines as an important tool in the fight against cancer. The aim of this approach is to reduce cancer occurrence by inducing a specific immune response targeting tumours at an early stage before they can fully develop. The great advantage of preventive cancer vaccines lies in the potential to harness a less-compromised immune system in vaccine recipients before their immune responses become affected by the advanced status of the disease itself or by aggressive treatments such as chemotherapy. Successful implementation of immunoprevention against oncogenic viruses such as hepatitis B and papillomavirus has led to a dramatic decrease in virally induced cancers. Extending this approach to other cancers holds great promise but remains a major challenge. Here, we provide a comprehensive review of preclinical evidence supporting this approach, encouraging results from pioneering clinical studies as well as a discussion on the key aspects and open questions to address in order to design potent prophylactic cancer vaccines in the near future.

The recent experiences with the pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have demonstrated the urgent need for a structured approach towards accelerated and more effective discovery, development and delivery of vaccines, therapeutics, and diagnostics to minimize the overall impact of the next pandemic (see Related links). This urgency is further highlighted by the recent World Health Organization (WHO) declaration of a public health emergency of international concern for mpox (see Related links).

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe subgroup metabolic dysfunction-associated steatohepatitis (MASH) have become a global epidemic and are driven by chronic overnutrition and multiple genetic susceptibility factors. The physiological outcomes include hepatocyte death, liver inflammation and cirrhosis. The first therapeutic for MASLD and MASH, resmetirom, has recently been approved for clinical use and has energized this therapeutic space. However, there is still much to learn in clinical studies of MASH, such as the scale of placebo responses, optimal trial end points, the time required for fibrosis reversal and side effect profiles. This Review introduces aspects of disease pathogenesis related to drug development and discusses two main therapeutic approaches. Thyroid hormone receptor-β agonists, such as resmetirom, as well as fatty acid synthase inhibitors, target the liver and enable it to function within a toxic metabolic environment. In parallel, incretin analogues such as semaglutide improve metabolism, allowing the liver to self-regulate and reversing many aspects of MASH. We also discuss how combinations of therapeutics could potentially be used to treat patients.

Lysine acetylation is a major post-translational modification in histones and other proteins that is catalysed by the ‘writer’ lysine acetyltransferases (KATs) and mediates interactions with bromodomains (BrDs) and other ‘reader’ proteins. KATs and BrDs play key roles in regulating gene expression, cell growth, chromatin structure, and epigenetics and are often dysregulated in disease states, including cancer. There have been accelerating efforts to identify potent and selective small molecules that can target individual KATs and BrDs with the goal of developing new therapeutics, and some of these agents are in clinical trials. Here, we summarize the different families of KATs and BrDs, discuss their functions and structures, and highlight key advances in the design and development of chemical agents that show promise in blocking the action of these chromatin proteins for disease treatment.