Pub Date : 2025-09-17DOI: 10.1038/s41573-025-01280-8
Linda Zhang, Jiangbo Wei, Zhongyu Zou, Chuan He
Ribonucleotide bases can be chemically modified by cellular enzymes such as methyltransferases to regulate RNA metabolism and biological processes. The association between abnormal levels of RNA modification effector proteins and human diseases has spurred interest in therapeutic targeting of RNA modification systems, and an agent that inhibits the RNA-methylating enzyme METTL3 has entered clinical trials. Despite the promise of these pathways, therapeutic agents targeting proteins that write, read and erase RNA modifications are still limited. In this Review, we describe the cellular functions and disease associations of proteins that regulate RNA modifications. We focus on the N6-methyladenosine pathway, highlighting early-stage advances in inhibitor development such as against the YTH reader proteins, but we also discuss the potential of targeting other RNA modification pathways. Targeting RNA modification systems offers a new strategy for treating cancer, improving immunotherapy and enhancing stem cell therapies. RNA can be chemically modified by enzymes such as methyltransferases to regulate RNA metabolism, gene expression and other biological processes. This Review mainly focuses on the disease-relevant N6-methyladenosine RNA modification pathway and discusses efforts to therapeutically target N6-methyladenosine writer, eraser and reader proteins.
{"title":"RNA modification systems as therapeutic targets","authors":"Linda Zhang, Jiangbo Wei, Zhongyu Zou, Chuan He","doi":"10.1038/s41573-025-01280-8","DOIUrl":"10.1038/s41573-025-01280-8","url":null,"abstract":"Ribonucleotide bases can be chemically modified by cellular enzymes such as methyltransferases to regulate RNA metabolism and biological processes. The association between abnormal levels of RNA modification effector proteins and human diseases has spurred interest in therapeutic targeting of RNA modification systems, and an agent that inhibits the RNA-methylating enzyme METTL3 has entered clinical trials. Despite the promise of these pathways, therapeutic agents targeting proteins that write, read and erase RNA modifications are still limited. In this Review, we describe the cellular functions and disease associations of proteins that regulate RNA modifications. We focus on the N6-methyladenosine pathway, highlighting early-stage advances in inhibitor development such as against the YTH reader proteins, but we also discuss the potential of targeting other RNA modification pathways. Targeting RNA modification systems offers a new strategy for treating cancer, improving immunotherapy and enhancing stem cell therapies. RNA can be chemically modified by enzymes such as methyltransferases to regulate RNA metabolism, gene expression and other biological processes. This Review mainly focuses on the disease-relevant N6-methyladenosine RNA modification pathway and discusses efforts to therapeutically target N6-methyladenosine writer, eraser and reader proteins.","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"25 1","pages":"59-78"},"PeriodicalIF":101.8,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145078277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-15DOI: 10.1038/d41573-025-00152-5
Kaniaw Dilzer
{"title":"Upcoming FDA approval decisions in Q4 2025","authors":"Kaniaw Dilzer","doi":"10.1038/d41573-025-00152-5","DOIUrl":"10.1038/d41573-025-00152-5","url":null,"abstract":"","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"24 10","pages":"735-735"},"PeriodicalIF":101.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/d41573-025-00152-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-15DOI: 10.1038/s41573-025-01268-4
Zongjie Wang, Claire Liu, Kangfu Chen, Joseph Song, Shana O. Kelley
Immunotherapies have transformed the treatment of many cancers and autoimmune diseases. However, durable therapeutic benefits are achieved in only certain subsets of patients. Due to the complexity and heterogeneity of disease, it remains challenging to design effective immunotherapies and predict their effects. Microscale systems — including microfluidics, microelectronics and microscaffolds — are now being adapted to accelerate immunotherapy discovery and development, with the potential to address efficacy, toxicity, predictability and affordability challenges. These microsystems consist of miniaturized structures, sensors and actuators that can manipulate molecules and cells of the immune system with high accuracy and throughput. Advances facilitated by microsystem technologies relevant to the discovery and translation of key types of immunotherapy (monoclonal antibodies, cytokine-based drugs, engineered immune cells and therapeutic vaccines) include the development of high-throughput devices for functional selection, miniaturized bioreactors for biomanufacturing, engineered scaffolds for therapeutic administration and sensitive biosensors for immune surveillance post-administration. Challenges facing the clinical translation of microsystem-based immunotherapies include issues related to standardization and integration as well as the need for new regulatory guidance. The potential of microsystem technologies to accelerate the development and clinical translation of immunotherapies is now being realized. This Review discusses recent advances in microsystem technologies, illustrating how their application can address key challenges related to the efficacy, toxicity, predictability and affordability of immunotherapeutics. Future directions and ongoing challenges facing the clinical translation of these technologies are discussed.
{"title":"Microsystem technologies for accelerating the discovery and translation of immunotherapies","authors":"Zongjie Wang, Claire Liu, Kangfu Chen, Joseph Song, Shana O. Kelley","doi":"10.1038/s41573-025-01268-4","DOIUrl":"10.1038/s41573-025-01268-4","url":null,"abstract":"Immunotherapies have transformed the treatment of many cancers and autoimmune diseases. However, durable therapeutic benefits are achieved in only certain subsets of patients. Due to the complexity and heterogeneity of disease, it remains challenging to design effective immunotherapies and predict their effects. Microscale systems — including microfluidics, microelectronics and microscaffolds — are now being adapted to accelerate immunotherapy discovery and development, with the potential to address efficacy, toxicity, predictability and affordability challenges. These microsystems consist of miniaturized structures, sensors and actuators that can manipulate molecules and cells of the immune system with high accuracy and throughput. Advances facilitated by microsystem technologies relevant to the discovery and translation of key types of immunotherapy (monoclonal antibodies, cytokine-based drugs, engineered immune cells and therapeutic vaccines) include the development of high-throughput devices for functional selection, miniaturized bioreactors for biomanufacturing, engineered scaffolds for therapeutic administration and sensitive biosensors for immune surveillance post-administration. Challenges facing the clinical translation of microsystem-based immunotherapies include issues related to standardization and integration as well as the need for new regulatory guidance. The potential of microsystem technologies to accelerate the development and clinical translation of immunotherapies is now being realized. This Review discusses recent advances in microsystem technologies, illustrating how their application can address key challenges related to the efficacy, toxicity, predictability and affordability of immunotherapeutics. Future directions and ongoing challenges facing the clinical translation of these technologies are discussed. ","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"25 1","pages":"39-58"},"PeriodicalIF":101.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-12DOI: 10.1038/d41573-025-00154-3
Asher Mullard
Lynda Stuart, president and CEO of the newly launched Fund for Science and Technology, discusses the philanthropic organization’s plans for bioscience and AI. Lynda Stuart, president and CEO of the newly launched Fund for Science and Technology, discusses the philanthropic organization’s plans for bioscience and AI.
{"title":"New US$3.1 billion foundation takes big, long-term bets on bioscience, AI and the environment","authors":"Asher Mullard","doi":"10.1038/d41573-025-00154-3","DOIUrl":"10.1038/d41573-025-00154-3","url":null,"abstract":"Lynda Stuart, president and CEO of the newly launched Fund for Science and Technology, discusses the philanthropic organization’s plans for bioscience and AI. Lynda Stuart, president and CEO of the newly launched Fund for Science and Technology, discusses the philanthropic organization’s plans for bioscience and AI.","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"24 10","pages":"736-737"},"PeriodicalIF":101.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/d41573-025-00154-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-12DOI: 10.1038/d41573-025-00153-4
Xiangyun Mao, Yi Li, Aaron S. Kesselheim, Yi Ba, Guanqiao Li
{"title":"Breakthrough therapy designations in China and the United States","authors":"Xiangyun Mao, \u0000 Yi Li, \u0000 Aaron S. Kesselheim, \u0000 Yi Ba, \u0000 Guanqiao Li","doi":"10.1038/d41573-025-00153-4","DOIUrl":"10.1038/d41573-025-00153-4","url":null,"abstract":"","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"24 10","pages":"733-734"},"PeriodicalIF":101.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/d41573-025-00153-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-11DOI: 10.1038/s41573-025-01273-7
Emanuel Gonçalves, Colm J. Ryan, David J. Adams
Synthetic lethality, first proposed more than two decades ago, has long held immense promise for targeted cancer therapy. Although the clinical success of PARP inhibition in BRCA-mutant cancers stands as proof of concept, few other synthetic lethal interactions have been translated from preclinical findings into effective therapies. This slow pace of translation stems in part from the difficulty of developing drugs against genetic dependencies, but also reflects the cell- and tissue-specific nature of these interactions. In this Review, we outline recent advances in the discovery and validation of synthetic lethal pairs, from their discovery in large-scale genetic screens to the development of drugs for the clinic. We discuss how alternative CRISPR-based approaches — including combinatorial screens, base editing and saturation mutagenesis — are now being used to discover new tractable interactions. We also examine how machine learning models can enable prioritization of candidate pairs and the identification of biomarkers for patient stratification. Finally, we highlight alternative phenotypic readouts, such as high-content imaging and single-cell profiling, which enable the dissection of phenotypes beyond simple cell growth or fitness. Together, these developments are refining the synthetic lethality paradigm and advancing its potential for cancer therapy. This Review outlines recent advances in synthetic lethality, from CRISPR-based discovery and machine learning-guided prioritization of gene pairs to new phenotypic readouts, highlighting emerging strategies to overcome translational barriers and unlock the therapeutic potential of targeting context-specific genetic dependencies in cancer.
{"title":"Synthetic lethality in cancer drug discovery: challenges and opportunities","authors":"Emanuel Gonçalves, Colm J. Ryan, David J. Adams","doi":"10.1038/s41573-025-01273-7","DOIUrl":"10.1038/s41573-025-01273-7","url":null,"abstract":"Synthetic lethality, first proposed more than two decades ago, has long held immense promise for targeted cancer therapy. Although the clinical success of PARP inhibition in BRCA-mutant cancers stands as proof of concept, few other synthetic lethal interactions have been translated from preclinical findings into effective therapies. This slow pace of translation stems in part from the difficulty of developing drugs against genetic dependencies, but also reflects the cell- and tissue-specific nature of these interactions. In this Review, we outline recent advances in the discovery and validation of synthetic lethal pairs, from their discovery in large-scale genetic screens to the development of drugs for the clinic. We discuss how alternative CRISPR-based approaches — including combinatorial screens, base editing and saturation mutagenesis — are now being used to discover new tractable interactions. We also examine how machine learning models can enable prioritization of candidate pairs and the identification of biomarkers for patient stratification. Finally, we highlight alternative phenotypic readouts, such as high-content imaging and single-cell profiling, which enable the dissection of phenotypes beyond simple cell growth or fitness. Together, these developments are refining the synthetic lethality paradigm and advancing its potential for cancer therapy. This Review outlines recent advances in synthetic lethality, from CRISPR-based discovery and machine learning-guided prioritization of gene pairs to new phenotypic readouts, highlighting emerging strategies to overcome translational barriers and unlock the therapeutic potential of targeting context-specific genetic dependencies in cancer.","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"25 1","pages":"22-38"},"PeriodicalIF":101.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-08DOI: 10.1038/d41573-025-00150-7
Asher Mullard
{"title":"Novel drug candidates for hard-to-treat hypertension vie for blockbuster positioning","authors":"Asher Mullard","doi":"10.1038/d41573-025-00150-7","DOIUrl":"10.1038/d41573-025-00150-7","url":null,"abstract":"","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"24 10","pages":"731-731"},"PeriodicalIF":101.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/d41573-025-00150-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-08DOI: 10.1038/d41573-025-00151-6
Asher Mullard
{"title":"FDA approves anti-prekallikrein drug for hereditary angioedema","authors":"Asher Mullard","doi":"10.1038/d41573-025-00151-6","DOIUrl":"10.1038/d41573-025-00151-6","url":null,"abstract":"","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"24 10","pages":"732-732"},"PeriodicalIF":101.8,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/d41573-025-00151-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145009260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-05DOI: 10.1038/d41573-025-00149-0
Asher Mullard
{"title":"AbbVie bets on psychedelic drugs in Gilgamesh buy out","authors":"Asher Mullard","doi":"10.1038/d41573-025-00149-0","DOIUrl":"10.1038/d41573-025-00149-0","url":null,"abstract":"","PeriodicalId":19068,"journal":{"name":"Nature Reviews. Drug Discovery","volume":"24 10","pages":"732-732"},"PeriodicalIF":101.8,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/d41573-025-00149-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144995212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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