Signal Transduction and Targeted Therapy最新文献

{"title":"VCP downstream metabolite glycerol-3-phosphate (G3P) inhibits CD8+T cells function in the HCC microenvironment","authors":"Cheng Cheng, Qingrui Zha, Linmao Sun, Tianming Cui, Xinyu Guo, Changjian Xing, Zhengxiang Chen, Changyong Ji, Shuhang Liang, Shengwei Tao, Junhui Chu, Chenghui Wu, Qi Chu, Xuetian Gu, Ning Zhang, Yumin Fu, Shumin Deng, Yitong Zhu, Jiabei Wang, Yao Liu, Lianxin Liu","doi":"10.1038/s41392-024-02120-8","DOIUrl":"https://doi.org/10.1038/s41392-024-02120-8","url":null,"abstract":"<p>CD8⁺T cells within the tumor microenvironment (TME) are often functionally impaired, which limits their ability to mount effective anti-tumor responses. However, the molecular mechanisms behind this dysfunction remain incompletely understood. Here, we identified valosin-containing protein (VCP) as a key regulator of CD8⁺T cells suppression in hepatocellular carcinoma (HCC). Our findings reveal that VCP suppresses the activation, expansion, and cytotoxic capacity of CD8⁺T cells both in vitro and in vivo, significantly contributing to the immunosuppressive nature of the TME. Mechanistically, VCP stabilizes the expression of glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L), leading to the accumulation of glycerol-3-phosphate (G3P), a downstream metabolite of GPD1L. The accumulated G3P diffuses into the TME and directly interacts with SRC-family tyrosine kinase LCK, a critical component of the T-cell receptor (TCR) signaling pathway in CD8⁺T cells. This interaction heightens the phosphorylation of Tyr505, a key inhibitory residue, ultimately reducing LCK activity and impairing downstream TCR signaling. Consequently, CD8⁺T cells lose their functional capacity, diminishing their ability to fight against HCC. Importantly, we demonstrated that targeting VCP in combination with anti-PD1 therapy significantly suppresses HCC tumor growth and restores the anti-tumor function of CD8⁺T cells, suggesting synergistic therapeutic potential. These findings highlight a previously unrecognized mechanism involving VCP and G3P in suppressing T-cell-mediated immunity in the TME, positioning VCP as a promising upstream target for enhancing immunotherapy in HCC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"74 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026908","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":"Artificial intelligence propels lung cancer screening: innovations and the challenges of explainability and reproducibility","authors":"Mario Mascalchi, Chiara Marzi, Stefano Diciotti","doi":"10.1038/s41392-024-02111-9","DOIUrl":"https://doi.org/10.1038/s41392-024-02111-9","url":null,"abstract":"<p>In a recent study published in <i>Nature Medicine</i>, Wang, Shao, and colleagues successfully addressed two critical issues of lung cancer (LC) screening with low-dose computed tomography (LDCT) whose widespread implementation, despite its capacity to decrease LC mortality, remains challenging: (1) the difficulty in accurately distinguishing malignant nodules from the far more common benign nodules detected on LDCT, and (2) the insufficient coverage of LC screening in resource-limited areas.¹</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"108 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026685","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":"Roles of human papillomavirus in cancers: oncogenic mechanisms and clinical use","authors":"Yu Zhang, Ke Qiu, Jianjun Ren, Yu Zhao, Ping Cheng","doi":"10.1038/s41392-024-02083-w","DOIUrl":"https://doi.org/10.1038/s41392-024-02083-w","url":null,"abstract":"<p>Human papillomaviruses, particularly high-risk human papillomaviruses, have been universally considered to be associated with the oncogenesis and progression of various cancers. The genome of human papillomaviruses is circular, double-stranded DNA that encodes early and late proteins. Each of the proteins is of crucial significance in infecting the epithelium of host cells persistently and supporting viral genome integrating into host cells. Notably, E6 and E7 proteins, classified as oncoproteins, trigger the incidence of cancers by fostering cell proliferation, hindering apoptosis, evading immune surveillance, promoting cell invasion, and disrupting the balance of cellular metabolism. Therefore, targeting human papillomaviruses and decoding molecular mechanisms by which human papillomaviruses drive carcinogenesis are of great necessity to better treat human papillomaviruses-related cancers. Human papillomaviruses have been applied clinically to different facets of human papillomavirus-related cancers, including prevention, screening, diagnosis, treatment, and prognosis. Several types of prophylactic vaccines have been publicly utilized worldwide and have greatly decreased the occurrence of human papillomavirus-related cancers, which have benefited numerous people. Although various therapeutic vaccines have been developed and tested clinically, none of them have been officially approved to date. Enhancing the efficacy of vaccines and searching for innovative technologies targeting human papillomaviruses remain critical challenges that warrant continuous research and attention in the future.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"13 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026906","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":"Immunotherapy in ovarian cancer: spatial functional genomics to unravel resistance mechanisms","authors":"Martina Rausch, Karlotta Bartels, Josef Leibold","doi":"10.1038/s41392-024-02110-w","DOIUrl":"https://doi.org/10.1038/s41392-024-02110-w","url":null,"abstract":"<p>The recent publication by Mollaoglu et al.¹ in <i>Cell</i> reveals an unexpected role for tumor derived IL4 in driving immunotherapy resistance in ovarian cancer (OvCa). This finding nominates the combination of immunotherapy and IL4-signaling targeting strategies as a promising new approach for the treatment of advanced OvCa.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"45 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991986","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":"Targeting SRSF1 improves cancer immunotherapy by dually acting on CD8+T and tumor cells","authors":"Gui-Qi Zhu, Zheng Tang, Tian-Hao Chu, Biao Wang, Shi-Ping Chen, Chen-Yang Tao, Jia-Liang Cai, Rui Yang, Wei-Feng Qu, Yi Wang, Qian-Fu Zhao, Run Huang, Meng-Xin Tian, Yuan Fang, Jun Gao, Xiao-Ling Wu, Jian Zhou, Wei-Ren Liu, Zhi Dai, Ying-Hong Shi, Jia Fan","doi":"10.1038/s41392-024-02118-2","DOIUrl":"https://doi.org/10.1038/s41392-024-02118-2","url":null,"abstract":"<p>Serine arginine-rich splicing factor 1 (SRSF1) is a key oncogenic splicing factor in various cancers, promoting abnormal gene expression through post-translational regulation. Although the protumoral function of SRSF1 is well-established, the effects of inhibiting tumor-intrinsic SRSF1 on the tumor microenvironment and its impact on CD8⁺ T cell-mediated antitumor immunity remain unclear. Our findings indicate that depleting SRSF1 in CD8⁺ T cells improve antitumor immune function, glycolytic metabolism, and the efficacy of adoptive T cell therapy. The inactivation of SRSF1 in tumor cells reduces transcription factors, including c-Jun, c-myc, and JunB, facilitating glycolytic metabolism reprogramming, which restores CD8⁺ T cell function and inhibits tumor growth. The small-molecule inhibitor TN2008 targets SRSF1, boosting antitumor immune responses and improving immunotherapy effectiveness in mouse models. We therefore introduce a paradigm targeting SRSF1 that simultaneously disrupts tumor cell metabolism and enhances the antitumor immunity of CD8⁺ T cells.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"81 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991987","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":"Identification of glutamine as a potential therapeutic target in dry eye disease","authors":"Xiaoniao Chen, Chuyue Zhang, Fei Peng, Lingling Wu, Deyi Zhuo, Liqiang Wang, Min Zhang, Zhaohui Li, Lei Tian, Ying Jie, Yifei Huang, Xinji Yang, Xiaoqi Li, Fengyang Lei, Yu Cheng","doi":"10.1038/s41392-024-02119-1","DOIUrl":"https://doi.org/10.1038/s41392-024-02119-1","url":null,"abstract":"<p>Dry eye disease (DED) is a prevalent inflammatory condition significantly impacting quality of life, yet lacks effective pharmacological therapies. Herein, we proposed a novel approach to modulate the inflammation through metabolic remodeling, thus promoting dry eye recovery. Our study demonstrated that co-treatment with mesenchymal stem cells (MSCs) and thymosin beta-4 (Tβ4) yielded the best therapeutic outcome against dry eye, surpassing monotherapy outcomes. In situ metabolomics through matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) revealed increased glutamine levels in cornea following MSC + Tβ4 combined therapy. Inhibition of glutamine reversed the anti-inflammatory, anti-apoptotic, and homeostasis-preserving effects observed with combined therapy, highlighting the critical role of glutamine in dry eye therapy. Clinical cases and rodent model showed elevated expression of glutaminase (GLS1), an upstream enzyme in glutamine metabolism, following dry eye injury. Mechanistic studies indicated that overexpression and inhibition of GLS1 counteracted and enhanced, respectively, the anti-inflammatory effects of combined therapy, underscoring GLS1’s pivotal role in regulating glutamine metabolism. Furthermore, single-cell sequencing revealed a distinct subset of pro-inflammatory and pro-fibrotic corneal epithelial cells in the dry eye model, while glutamine treatment downregulated those subclusters, thereby reducing their inflammatory cytokine secretion. In summary, glutamine effectively ameliorated inflammation and the occurrence of apoptosis by downregulating the pro-inflammatory and pro-fibrotic corneal epithelial cells subclusters and the related IκBα/NF-κB signaling. The present study suggests that glutamine metabolism plays a critical, previously unrecognized role in DED and proposes an attractive strategy to enhance glutamine metabolism by inhibiting the enzyme GLS1 and thus alleviating inflammation-driven DED progression.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"8 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991988","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":"Preclinical CSF proteomic changes: a milestone in biomarker detection for autosomal dominant Alzheimer’s disease","authors":"J. Alexander Ross, Richard Dodel","doi":"10.1038/s41392-024-02109-3","DOIUrl":"https://doi.org/10.1038/s41392-024-02109-3","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"105 7S 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989861","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":"Dual targeting PD-L1 and 4-1BB to overcome dendritic cell-mediated lenalidomide resistance in follicular lymphoma","authors":"Zhong Zheng, Jian-Biao Wang, Rui Sun, Nan Wang, Xiang-Qin Weng, Tian-Yuan Xu, Di Fu, Yan Feng, Peng-Peng Xu, Shu Cheng, Li Wang, Yan Zhao, Bin Qu, Chuan-Xin Huang, Wei-Li Zhao","doi":"10.1038/s41392-024-02105-7","DOIUrl":"https://doi.org/10.1038/s41392-024-02105-7","url":null,"abstract":"<p>Immunomodulatory agent lenalidomide is effective in treating follicular lymphoma (FL). We conducted the first trial of immunotherapy rituximab plus lenalidomide in newly diagnosed FL in China (NCT03715309). One-hundred and fifteen patients were enrolled and treated with rituximab 375 mg/m² intravenously on day 0 and lenalidomide 25 mg orally on day 1–10 for 6 cycles of induction treatment, as well as lenalidomide for 6 cycles and rituximab for 8 cycles of maintenance treatment. We found that inferior progression-free survival of the patients was significantly associated with elevated serum β2m and lymph node &gt;6 cm, linking to decreased lymphoma cell autophagy and dendritic cell infiltration within the tumor microenvironment. PU.1 transcriptionally downregulated PD-L1 (Programmed death ligand 1) expression and upregulated 4-1BBL (4-1BB ligand) expression, increased lymphoma cell autophagy and dendritic cell maturation via PD-1/PD-L1 and 4-1BB/4-1BBL interaction. In vitro in co-culture system and in vivo in murine xenograft model, knockdown of PU.1 induced lenalidomide resistance, but sensitized FL cells to bi-specific PD-L1/4-1BB antibody or combined treatment of PD-L1 inhibitor and 4-1BB agonist. Collectively, PU.1 is essential in immunomodulatory effect of FL through PD-1/PD-L1- and 4-1BB/4-1BBL-mediated microenvironmental modulation. Dual targeting PD-L1 and 4-1BB could be an alternative immunotherapeutic strategy in the chemo-free era of FL treatment.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"37 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989856","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":"Isoxazole-based molecules restore NK cell immune surveillance in hepatocarcinogenesis by targeting TM4SF5 and SLAMF7 linkage","authors":"Ji Eon Kim, Hyun Su Kim, Wonsik Kim, Eun Hae Lee, Soyeon Kim, Taewoo Kim, Eun-Ae Shin, Kyung-hee Pyo, Haesong Lee, Seo Hee Jin, Jae-Ho Lee, Soo-Min Byeon, Dong Joo Kim, Jinwook Jeong, Jeongwon Lee, Minjae Ohn, Hyojung Lee, Su Jong Yu, Dongyun Shin, Semi Kim, Jun Yeob Yoo, Seung-Chul Lee, Young-Ger Suh, Jung Weon Lee","doi":"10.1038/s41392-024-02106-6","DOIUrl":"https://doi.org/10.1038/s41392-024-02106-6","url":null,"abstract":"<p>Dynamic communication between hepatocytes and the environment is critical in hepatocellular carcinoma (HCC) development. Clinical immunotherapy against HCC is currently unsatisfactory and needs more systemic considerations, including the identification of new biomarkers and immune checkpoints. Transmembrane 4 L six family member 5 (TM4SF5) is known to promote HCC, but it remains unclear how cancerous hepatocytes avoid immune surveillance and whether avoidance can be blocked. We investigated how TM4SF5-mediated hepatic tumorigenesis avoids surveillance by natural killer (NK) cells, which are prevalent in the liver, and whether the avoidance can be blocked by anti-TM4SF5 agents. We used comprehensive structure activity relationship analysis to identify TM4SF5-specific isoxazole (TSI)-based small molecules that inhibit TM4SF5-mediated effects. TM4SF5 expressed by hepatocytes reduced NK cell cytotoxicity by downregulating stimulatory ligands/receptors, including signaling lymphocytic activation molecule family member 7 (SLAMF7). TM4SF5 bound SLAMF7 depending on <i>N</i>-glycosylation and caused intracellular trafficking of SLAMF7 from the plasma membrane to lysosomes for degradation. TSI treatments in cell lines and animal models of HCC blocked this binding, intracellular trafficking, and downregulation, resulting in higher levels of stimulatory NK cell ligands. In mouse xenograft models, TSI treatment abrogated HCC development by increasing the abundance and dispersion of Slamf7-positive cells in liver tissues, recapitulating the phenotype of <i>Tm4sf5</i>-knockout mice and indicating TSI-mediated restoration of NK cell surveillance. These findings suggest that TSIs can inhibit TM4SF5-mediated liver carcinogenesis by increasing NK cell surveillance.</p><figure></figure>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"26 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989855","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":"Tissue-resident immune cells: from defining characteristics to roles in diseases","authors":"Jia Li, Chu Xiao, Chunxiang Li, Jie He","doi":"10.1038/s41392-024-02050-5","DOIUrl":"https://doi.org/10.1038/s41392-024-02050-5","url":null,"abstract":"<p>Tissue-resident immune cells (TRICs) are a highly heterogeneous and plastic subpopulation of immune cells that reside in lymphoid or peripheral tissues without recirculation. These cells are endowed with notably distinct capabilities, setting them apart from their circulating leukocyte counterparts. Many studies demonstrate their complex roles in both health and disease, involving the regulation of homeostasis, protection, and destruction. The advancement of tissue-resolution technologies, such as single-cell sequencing and spatiotemporal omics, provides deeper insights into the cell morphology, characteristic markers, and dynamic transcriptional profiles of TRICs. Currently, the reported TRIC population includes tissue-resident T cells, tissue-resident memory B (BRM) cells, tissue-resident innate lymphocytes, tissue-resident macrophages, tissue-resident neutrophils (TRNs), and tissue-resident mast cells, but unignorably the existence of TRNs is controversial. Previous studies focus on one of them in specific tissues or diseases, however, the origins, developmental trajectories, and intercellular cross-talks of every TRIC type are not fully summarized. In addition, a systemic overview of TRICs in disease progression and the development of parallel therapeutic strategies is lacking. Here, we describe the development and function characteristics of all TRIC types and their major roles in health and diseases. We shed light on how to harness TRICs to offer new therapeutic targets and present burning questions in this field.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"30 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987378","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}