Signal Transduction and Targeted Therapy最新文献

{"title":"Redox regulation: mechanisms, biology and therapeutic targets in diseases","authors":"Bowen Li, Hui Ming, Siyuan Qin, Edouard C. Nice, Jingsi Dong, Zhongyan Du, Canhua Huang","doi":"10.1038/s41392-024-02095-6","DOIUrl":"https://doi.org/10.1038/s41392-024-02095-6","url":null,"abstract":"<p>Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both the onset and progression of various diseases. Under physiological conditions, oxidative free radicals generated by the mitochondrial oxidative respiratory chain, endoplasmic reticulum, and NADPH oxidases can be effectively neutralized by NRF2-mediated antioxidant responses. These responses elevate the synthesis of superoxide dismutase (SOD), catalase, as well as key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption of this finely tuned equilibrium is closely linked to the pathogenesis of a wide range of diseases. Recent advances have broadened our understanding of the molecular mechanisms underpinning this dysregulation, highlighting the pivotal roles of genomic instability, epigenetic modifications, protein degradation, and metabolic reprogramming. These findings provide a foundation for exploring redox regulation as a mechanistic basis for improving therapeutic strategies. While antioxidant-based therapies have shown early promise in conditions where oxidative stress plays a primary pathological role, their efficacy in diseases characterized by complex, multifactorial etiologies remains controversial. A deeper, context-specific understanding of redox signaling, particularly the roles of redox-sensitive proteins, is critical for designing targeted therapies aimed at re-establishing redox balance. Emerging small molecule inhibitors that target specific cysteine residues in redox-sensitive proteins have demonstrated promising preclinical outcomes, setting the stage for forthcoming clinical trials. In this review, we summarize our current understanding of the intricate relationship between oxidative stress and disease pathogenesis and also discuss how these insights can be leveraged to optimize therapeutic strategies in clinical practice.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"17 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569360","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}

{"title":"Gut dysbiosis conveys psychological stress to activate LRP5/β-catenin pathway promoting cancer stemness","authors":"Bai Cui, Huandong Luo, Bin He, Xinyu Liu, Dekang Lv, Xiaoyu Zhang, Keyu Su, Sijia Zheng, Jinxin Lu, Cenxin Wang, Yuqing Yang, Zhuoran Zhao, Xianxian Liu, Xu Wang, Yingrui Zhao, Xiaoshan Nie, Yuanyuan Jiang, Ziyu Zhang, Congcong Liu, Xinyi Chen, Anqi Cai, Zhumeng Lv, Zhihang Liu, Fan An, Yunkun Zhang, Qiulong Yan, Keith W. Kelley, Guowang Xu, Lingzhi Xu, Quentin Liu, Fei Peng","doi":"10.1038/s41392-025-02159-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02159-1","url":null,"abstract":"<p>Psychological stress causes gut microbial dysbiosis and cancer progression, yet how gut microbiota determines psychological stress-induced tumor development remains unclear. Here we showed that psychological stress promotes breast tumor growth and cancer stemness, an outcome that depends on gut microbiota in germ-free and antibiotic-treated mice. Metagenomic and metabolomic analyses revealed that psychological stress markedly alters the composition and abundance of gut microbiota, especially <i>Akkermansia muciniphila</i> (<i>A. muciniphila</i>), and decreases short-chain fatty acid butyrate. Supplement of active <i>A. muciniphila</i>, butyrate or a butyrate-producing high fiber diet dramatically reversed the oncogenic property and anxiety-like behavior of psychological stress in a murine spontaneous tumor model or an orthotopic tumor model. Mechanistically, RNA sequencing analysis screened out that butyrate decreases LRP5 expression to block the activation of Wnt/β-catenin signaling pathway, dampening breast cancer stemness. Moreover, butyrate as a HDAC inhibitor elevated histone H3K9 acetylation level to transcriptionally activate ZFP36, which further accelerates LRP5 mRNA decay by binding adenine uridine-rich (AU-rich) elements of LRP5 transcript. Clinically, fecal <i>A. muciniphila</i> and serum butyrate were inversely correlated with tumoral LRP5/β-catenin expression, poor prognosis and negative mood in breast cancer patients. Altogether, our findings uncover a microbiota-dependent mechanism of psychological stress-triggered cancer stemness, and provide both clinical biomarkers and potential therapeutic avenues for cancer patients undergoing psychological stress.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"16 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545917","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}

{"title":"Metaplastic epithelial cells: origination from stem cells and promotion of intestinal inflammation","authors":"Tim Holland, Jochen Mattner","doi":"10.1038/s41392-025-02165-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02165-3","url":null,"abstract":"<p>In a recent paper published in <i>Nature</i>, Oliver and colleagues report that pyloric gland metaplastic cells within the intestinal epithelium arise from crypt-based stem cells in response to chronic inflammatory irritation.¹ These metaplastic cells to which the authors refer to as INFLAREs exhibit unique transcriptional signatures and promote inflammation-mediated tissue remodeling.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546066","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}

{"title":"Advance in peptide-based drug development: delivery platforms, therapeutics and vaccines","authors":"Wenjing Xiao, Wenjie Jiang, Zheng Chen, Yu Huang, Junyi Mao, Wei Zheng, Yonghe Hu, Jianyou Shi","doi":"10.1038/s41392-024-02107-5","DOIUrl":"https://doi.org/10.1038/s41392-024-02107-5","url":null,"abstract":"<p>The successful approval of peptide-based drugs can be attributed to a collaborative effort across multiple disciplines. The integration of novel drug design and synthesis techniques, display library technology, delivery systems, bioengineering advancements, and artificial intelligence have significantly expedited the development of groundbreaking peptide-based drugs, effectively addressing the obstacles associated with their character, such as the rapid clearance and degradation, necessitating subcutaneous injection leading to increasing patient discomfort, and ultimately advancing translational research efforts. Peptides are presently employed in the management and diagnosis of a diverse array of medical conditions, such as diabetes mellitus, weight loss, oncology, and rare diseases, and are additionally garnering interest in facilitating targeted drug delivery platforms and the advancement of peptide-based vaccines. This paper provides an overview of the present market and clinical trial progress of peptide-based therapeutics, delivery platforms, and vaccines. It examines the key areas of research in peptide-based drug development through a literature analysis and emphasizes the structural modification principles of peptide-based drugs, as well as the recent advancements in screening, design, and delivery technologies. The accelerated advancement in the development of novel peptide-based therapeutics, including peptide-drug complexes, new peptide-based vaccines, and innovative peptide-based diagnostic reagents, has the potential to promote the era of precise customization of disease therapeutic schedule.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"29 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545883","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}

{"title":"Correction to: TIFA suppresses hepatocellular carcinoma progression via MALT1-dependent and -independent signaling pathways","authors":"Wenzhi Shen, Renle Du, Jun Li, Xiaohe Luo, Shuangtao Zhao, Antao Chang, Wei Zhou, Ruifang Gao, Dehong Luo, Juan Wang, Na Hao, Yanhua Liu, Yanan Chen, Yunping Luo, Peiqing Sun, Shengyong Yang, Na Luo, Rong Xiang","doi":"10.1038/s41392-025-02187-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02187-x","url":null,"abstract":"<p>Correction to: <i>Signal Transduction and Targeted Therapy</i> https://doi.org/10.1038/sigtrans.2016.13, published online 22 July 2016</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"16 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143538601","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}

{"title":"Unveiling the hidden ally: Blastocystis links healthier diets and cardiometabolic benefits","authors":"Lei Deng, Kevin S. W. Tan","doi":"10.1038/s41392-025-02146-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02146-6","url":null,"abstract":"<p>In a recent study published in <i>Cell</i>,¹ Piperni and colleagues revealed that <i>Blastocystis</i> prevalence varies significantly across geographic regions and lifestyles, with higher carriage linked to healthier plant-based diets and favorable cardiometabolic profiles. These findings position <i>Blastocystis</i> as a potential biomarker for gut health and metabolic well-being, challenging its traditional perception as a pathogen (Fig. 1).</p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 1</b></figcaption><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-025-02146-6/MediaObjects/41392_2025_2146_Fig1_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"426\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-025-02146-6/MediaObjects/41392_2025_2146_Fig1_HTML.png\" width=\"685\"/></picture><p>Global prevalence, dietary associations, and potential health implications of <i>Blastocystis</i>. <b>a</b> The analysis included metagenomic sequencing of stool samples from 56,989 individuals across 32 countries, accompanied by dietary and metabolic metadata. High-throughput sequencing and machine learning models (random forest) were employed to predict <i>Blastocystis</i> presence. The bar chart illustrates the geographic variability in <i>Blastocystis</i> prevalence (adapted from Piperni et al.). Fiji exhibited the highest prevalence (56.29%), while Japan had the lowest (2.46%). Subtypes (STs) varied by region, with ST1 and ST2 dominating in non-Westernized populations and ST4 more common in Europe. <b>b</b> The association of <i>Blastocystis</i> carriage with plant-based foods promotes gut health and correlates with increased <i>Blastocystis</i> abundance. It highlights the potential effects of <i>Blastocystis</i> on gut microbiome diversity, microbial metabolite production (e.g., SCFAs, BAs, tryptophan derivatives), and intestinal barrier integrity, which collectively contribute to favorable cardiometabolic biomarkers. Created with Biorender.com</p><span>Full size image</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"66 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532765","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}

{"title":"Neoleukin-2/15-armored CAR-NK cells sustain superior therapeutic efficacy in solid tumors via c-Myc/NRF1 activation","authors":"Jianhua Luo, Meng Guo, Mingyan Huang, Yanfang Liu, Yuping Qian, Qiuyan Liu, Xuetao Cao","doi":"10.1038/s41392-025-02158-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02158-2","url":null,"abstract":"<p>Adoptive transfer of chimeric antigen receptor (CAR)-modified natural killer (NK) cells represents a transformative approach that has significantly advanced clinical outcomes in patients with malignant hematological conditions. However, the efficacy of CAR-NK cells in treating solid tumors is limited by their exhaustion, impaired infiltration and poor persistence in the immunosuppressive tumor microenvironment (TME). As NK cell functional states are associated with IL-2 cascade, we engineered mesothelin-specific CAR-NK cells that secrete neoleukin-2/15 (Neo-2/15), an IL-2Rβγ agonist, to resist immunosuppressive polarization within TME. The adoptively transferred Neo-2/15-armored CAR-NK cells exhibited enhanced cytotoxicity, less exhaustion and longer persistence within TME, thereby having superior antitumor activity against pancreatic cancer and ovarian cancer. Mechanistically, Neo-2/15 provided sustained and enhanced downstream IL-2 receptor signaling, which promotes the expression of c-Myc and nuclear respiratory factor 1 (NRF1) in CAR-NK cells. This upregulation was crucial for maintaining mitochondrial adaptability and metabolic resilience, ultimately leading to increased cytotoxicity and pronounced persistence of CAR-NK cells within the TME. The resistance against TME immunosuppressive polarization necessitated the upregulation of NRF1, which is essential to the augmentative effects elicited by Neo-2/15. Overexpression of NRF1 significantly bolsters the antitumor efficacy of CAR-NK cells both in vitro and in vivo, with increased ATP production. Collectively, Neo-2/15-expressing CAR-NK cells exerts superior antitumor effects by exhaustion-resistance and longer survival in solid tumors.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"34 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532766","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}

{"title":"Ultra-high dose rate radiotherapy overcomes radioresistance in head and neck squamous cell carcinoma","authors":"Hong-Shuai Li, Ruo Tang, Hua-Shan Shi, Zi-Jian Qin, Xiao-Yang Zhang, Yun-Fei Sun, Zhi-Gong Wei, Chao-Fan Ma, Liu Yang, Ye Chen, Zhe-Ran Liu, Li-Li Zhu, Wen Yang, Li Yang, Ai-Ning Xu, Zhuo Zhang, Shu-Qing Liao, Jin-Shui Shi, Jian-Jun Deng, Xiao-Zhong He, Xing-Chen Peng","doi":"10.1038/s41392-025-02184-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02184-0","url":null,"abstract":"<p>Radiotherapy (RT) resistance in head and neck squamous cell carcinoma (HNSCC) significantly hampers local control and patient prognosis. This study investigated the efficacy and molecular mechanisms of high-energy X-ray-based ultra-high dose rate radiotherapy (UHDR-RT) in overcoming RT resistance. The established RT-resistant HNSCC cell lines and animal models were subjected to UHDR-RT or conventional RT (Conv-RT) via a high-power rhodotron accelerator. Cellular assays assessed the malignant phenotype, viability, and degree of DNA damage, whereas in vivo evaluations focused on tumor proliferation and the tumor immune microenvironment (TiME). Transcriptome sequencing and Olink proteomics were employed to explore the underlying mechanisms involved. In vitro experiments indicated that UHDR-RT suppressed radioresistant cell proliferation and invasion, while promoting apoptosis and exacerbating DNA damage. In contrast, its efficacy in radiosensitive cells was comparable to that of Conv-RT. In vivo studies using patient-derived xenograft nude mice models demonstrated that UHDR-RT only partially reversed RT resistance. Transcriptomic and proteomic analyses of C57BL/6J mice models revealed the predominant role of TiME modulating in reversing radioresistance. Immunofluorescence and flow cytometry confirmed increased CD8⁺ T cells and an increased M1/M2 macrophage ratio post-UHDR-RT. Mechanistically, UHDR-RT activated CD8⁺ T cells, which stimulated M1 macrophages through paracrine IFN-γ signaling, thereby enhancing TiME activation. Furthermore, the activated M1 macrophages secreted CXCL9, which in turn reactivated CD8⁺ T cells, forming a feedforward loop that amplified TiME activation. This study elucidates the dual role of UHDR-RT in directly inducing DNA damage and modulating the TiME, highlighting its potential in treating radioresistant HNSCC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"36 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532795","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}

{"title":"Engineered mitochondria in diseases: mechanisms, strategies, and applications","authors":"Mingyang Li, Limin Wu, Haibo Si, Yuangang Wu, Yuan Liu, Yi Zeng, Bin Shen","doi":"10.1038/s41392-024-02081-y","DOIUrl":"https://doi.org/10.1038/s41392-024-02081-y","url":null,"abstract":"<p>Mitochondrial diseases represent one of the most prevalent and debilitating categories of hereditary disorders, characterized by significant genetic, biological, and clinical heterogeneity, which has driven the development of the field of engineered mitochondria. With the growing recognition of the pathogenic role of damaged mitochondria in aging, oxidative disorders, inflammatory diseases, and cancer, the application of engineered mitochondria has expanded to those non-hereditary contexts (sometimes referred to as mitochondria-related diseases). Due to their unique non-eukaryotic origins and endosymbiotic relationship, mitochondria are considered highly suitable for gene editing and intercellular transplantation, and remarkable progress has been achieved in two promising therapeutic strategies—mitochondrial gene editing and artificial mitochondrial transfer (collectively referred to as engineered mitochondria in this review) over the past two decades. Here, we provide a comprehensive review of the mechanisms and recent advancements in the development of engineered mitochondria for therapeutic applications, alongside a concise summary of potential clinical implications and supporting evidence from preclinical and clinical studies. Additionally, an emerging and potentially feasible approach involves ex vivo mitochondrial editing, followed by selection and transplantation, which holds the potential to overcome limitations such as reduced in vivo operability and the introduction of allogeneic mitochondrial heterogeneity, thereby broadening the applicability of engineered mitochondria.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"5 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532763","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}

{"title":"Safety, pharmacokinetics and efficacy of HA121-28 in patients with advanced solid tumors and RET fusion-positive non-small-cell lung cancer: a multicenter, open-label, single-arm phase 1/2 trial","authors":"Dan-Yun Ruan, Wen-Wen Huang, Yongsheng Li, Yanqiu Zhao, Yehui Shi, Yuming Jia, Shundong Cang, Wei Zhang, Jianhua Shi, Jun Chen, Jie Lin, Yunpeng Liu, Jianming Xu, Weiwei Ouyang, Jian Fang, Wu Zhuang, Caigang Liu, Qing Bu, Manxiang Li, Xiangjiao Meng, Meili Sun, Nong Yang, Xiaorong Dong, Yueyin Pan, Xingya Li, Xiujuan Qu, Tongmei Zhang, Xianglin Yuan, Sheng Hu, Wei Guo, Yalun Li, Shengqing Li, Dongying Liu, Feixue Song, Liping Tan, Yan Yu, Xinmin Yu, Aimin Zang, Chang Sun, Qian Zhang, Kai Zou, Mo Dan, Rui-Hua Xu, Hongyun Zhao","doi":"10.1038/s41392-025-02155-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02155-5","url":null,"abstract":"<p>HA121-28, a promising multikinase inhibitor, mainly targets rearranged during transfection (RET) fusions and selectively targets vascular endothelial growth factor receptor-2, endothelial growth factor receptor, and fibroblast growth factor receptor 1-3. The safety, pharmacokinetics, and efficacy of HA121-28 were assessed in advanced solid tumors (phase 1, ClinicalTrials.gov NCT03994484) and advanced RET fusion-positive non-small-cell lung cancer (RET-TKI naive NSCLC, phase 2, ClinicalTrials.gov NCT05117658). HA121-28 was administered orally in doses range from 25 to 800 mg under the 21-day on/7-day off scheme for a 28-day cycle in phase 1 trial. The recommended dose identified in phase 1 (450 mg) was administered for patients during phase 2. The primary endpoints were the maximum tolerated dose (MTD) in phase 1 and the objective response rate (ORR) in phase 2. 162 patients were enrolled in phase 1 and 48 in phase 2. A total of 600 mg once daily was set as MTD. Across 100–800 mg, the exposure of HA121-28 increased in a dose-dependent manner. Consistent between both trials, diarrhea, rash, and prolonged QTc interval, were the most reported treatment-emergent adverse events. 40.0% (phase 1) and 62.5% (phase 2) patients experienced grade ≥3 treatment-related adverse events, respectively. The overall ORR was 26.8% and the median progression-free survival (PFS) was 5.5 months among 97 NSCLC patients with advanced RET fusion receiving a dose at ≥450 mg once daily. HA121-28 showed encouraging efficacy in advanced RET fusion NSCLC and its toxicity was tolerable in most patients. Nevertheless, cardiotoxicity is a notable concern that warrants careful attention.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"23 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517863","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}