Signal Transduction and Targeted Therapy最新文献

{"title":"Dual roles and therapeutic targeting of tumor-associated macrophages in tumor microenvironments","authors":"Jiasheng Xu, Lei Ding, Jianfeng Mei, Yeting Hu, Xiangxing Kong, Siqi Dai, Tongtong Bu, Qian Xiao, Kefeng Ding","doi":"10.1038/s41392-025-02325-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02325-5","url":null,"abstract":"<p>Tumor-associated macrophages (TAMs), derived from circulating monocytes recruited to tumor sites via chemotactic signals such as C-C motif ligand 2 (CCL2) and colony-stimulating factor-1 (CSF-1), are pivotal components of the tumor microenvironment (TME). Functionally polarized into distinct subtypes, TAMs play dual roles: proinflammatory M1-type TAMs enhance antitumor immunity through the secretion of cytokines such as interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-α) and direct tumor cell cytotoxicity, whereas M2-type TAMs promote tumor progression by facilitating angiogenesis, metastasis, and immunosuppression. This polarization is dynamically regulated by different cytokines, various signaling pathways, and metabolic cues within the TME. Spatial distribution analyses revealed that M2-like TAMs predominantly infiltrate hypoxic and stromal regions, where they secrete factors such as vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β), and matrix metalloproteinases (MMPs) to remodel the extracellular matrix and suppress immune responses via programmed death-ligand 1 (PD-L1) and arginase-1 upregulation. Crucially, TAMs interact extensively with immune cells; M2-TAMs secrete interleukin-10 (IL-10) and TGF-β to inhibit cytotoxic T lymphocytes while expanding regulatory T (Treg) cells and impairing natural killer (NK) cell function via altered antigen presentation. Conversely, M1-TAMs synergize with dendritic cells to enhance T-cell priming. Therapeutically, targeting TAMs offers promising strategies, including colony-stimulating factor-1 receptor (CSF-1R) inhibitors, CCL2 antagonists, and nanoparticle-mediated repolarization of M2-TAMs toward the M1 phenotype. Emerging genetic approaches, such as clustered regularly interspaced short palindromic repeat-CRISPR-associated protein 9 (CRISPR-Cas9) editing, aim to disrupt protumorigenic pathways in TAMs. Additionally, TAM-related biomarkers (e.g., CD206 and CD163) are being evaluated for their prognostic and predictive utility in immunotherapies. Despite progress, challenges persist owing to TAM plasticity and TME heterogeneity across cancers. This review synthesizes TAM biology, immune crosstalk, and therapeutic advancements, providing a foundation for novel oncology strategies aimed at reprogramming TAMs to overcome treatment resistance and improve clinical outcomes.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"44 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899050","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":"Mesenchymal stem cells in treating human diseases: molecular mechanisms and clinical studies","authors":"Xia Han, Rongdong Liao, Xiang Li, Cantong Zhang, Shaochuan Huo, Lei Qin, Yi Xiong, Tailin He, Guozhi Xiao, Tianfeng Zhang","doi":"10.1038/s41392-025-02313-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02313-9","url":null,"abstract":"<p>Mesenchymal stem cells (MSCs) have emerged as a highly promising strategy in regenerative medicine due to their self-renewal, pluripotency and immunomodulatory properties. MSCs are nonhematopoietic, multipotent stem cells that can differentiate into various mesodermal lineages and modulate the immune system. The therapeutic potential of MSCs from different tissues has been widely explored in preclinical models and clinical trials for human diseases, ranging from autoimmune diseases and inflammatory disorders to neurodegenerative diseases and orthopedic injuries. The therapeutic effects of MSCs can be mediated through the release of bioactive molecules, including growth factors, cytokines, and extracellular vesicles, which play crucial roles in modulating the local cellular environment, promoting tissue repair, angiogenesis, and cell survival, and exerting anti-inflammatory effects. MSCs can also interact with various immune cells, such as T cells, B cells, dendritic cells, and macrophages, modulating the immune response through both direct cell‒cell interactions and the release of immunoregulatory molecules. This review delves into the molecular mechanisms, signaling pathways, and regulatory factors that underpin the therapeutic effects of MSCs. This review also highlights the clinical applications and challenges associated with the use of MSC-based drugs to promote the safety and efficacy of MSC-based therapies. Overall, this comprehensive review provides valuable insights into the current state of MSC research and its potential for transforming the field of regenerative medicine as well as immune-mediated inflammatory diseases.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"22 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899056","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":"Hemoglobin as a pseudoperoxidase and drug target for oxidative stress-related diseases","authors":"Woojin Won, Elijah Hwejin Lee, Lizaveta Gotina, Heejung Chun, Jae-Hun Lee, Mridula Bhalla, Uiyeol Park, Daeun Kim, Tai Young Kim, Ji Won Choi, Yoowon Kim, Sun Jun Park, Jiwoon Lim, Jong-Hyun Park, Hyeon Jeong Kim, Jun Young Heo, Woosuk Chung, Myung Jin Oh, Hyun Joo An, Junghee Lee, Soo-Jin Oh, Hoon Ryu, Ae Nim Pae, Ki Duk Park, C. Justin Lee","doi":"10.1038/s41392-025-02366-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02366-w","url":null,"abstract":"<p>Hemoglobin (Hb) is well known for transporting oxygen in the blood, but its role in the brain remains poorly understood. Here, we identified Hb in the cytosol, mitochondria, and nuclei of hippocampal and substantia nigra astrocytes and dopaminergic neurons. As a pseudoperoxidase, Hb decomposes hydrogen peroxide (H₂O₂) and mitigates H₂O₂-induced oxidative damage. However, in Alzheimer’s disease, Parkinson’s disease, and aging, excessive H₂O₂ diminishes astrocytic Hb, perpetuating a vicious cycle of oxidative stress and neurodegeneration. To counter the harmful effects of aberrant H₂O₂ production in diseases, we developed KDS12025, a BBB-permeable small molecule that enhances Hb pseudoperoxidase activity 100-fold, even at a low level of Hb. KDS12025 and its analogs achieve this enhancement through its electron-donating amine group, possibly stabilizing the complex between Hb, H₂O₂, and KDS12025. KDS12025 reduces astrocytic H₂O₂, alleviates astrogliosis, normalizes Hb, and reverts to a virtuous cycle of redox balance, preventing neurodegeneration without altering the oxygen-transport function of Hb. Gene silencing of Hb abrogates the impact of KDS12025 in both culture and animal models, confirming the necessity of Hb for the effects of KDS12025. KDS12025 extends survival and improves motor function even in severe amyotrophic lateral sclerosis and aging. Furthermore, the enrichment of astrocytic Hb in the nucleolus highlights a novel antioxidative mechanism potentially protecting against nuclear oxidative damage. Our findings suggest that Hb is a new therapeutic target for neurodegenerative diseases, with KDS12025 emerging as a first-in-class approach that enhances Hb pseudoperoxidase activity to reduce H₂O₂. Increasing Hb pseudoperoxidase activity with KDS12025 mitigates oxidative stress and alleviates neurodegeneration in AD, PD, and ALS patients and increases the degree of aging, with broad applicability for numerous oxidative-stress-driven diseases.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"24 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899057","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":"A multicenter single-arm clinical study of Chinese children’s cancer group-acute promyelocytic leukemia-2017 (CCCG-APL-2017) protocol","authors":"Lixian Chang, Ju Gao, Xiaoying Lei, Yingyi He, Shuquan Zhuang, Chunhuai Li, Kaizhi Weng, Lingzhen Wang, Xia Guo, Qihui Liu, Pengfei Wang, Yong Zhuang, Mei Yan, Wei Liu, Hui Chen, Min Zhang, Shuhong Shen, Xiaofan Zhu, Xiuli Ju, Li Zhang, Zhuo Wang","doi":"10.1038/s41392-025-02353-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02353-1","url":null,"abstract":"<p>The Realgar-Indigo Naturalis formula (RIF) is a proprietary Chinese medicine, which is one of the important drugs in the treatment of pediatric acute promyelocytic leukemia (APL). However, the dose of RIF in clinical application is not uniform and the long-term effectiveness and safety of combining RIF with all-trans retinoic acid (ATRA) in a larger population of pediatric APL patients remains undocumented. We conducted a multicenter single-arm clinical trial (ChiCTR-OIC-16010014) in China. Individuals newly diagnosed with APL were treated with CCCG-APL-2017 protocol which is based on RIF and ATRA in consolidation. The event-free survival (EFS) and overall survival (OS) outcomes were evaluated. We recruited 200 patients diagnosed with APL. The six-year OS rate was 100% in the low-risk (LR) group and 97.6% in the high-risk (HR) group. The six-year EFS rate was 98.3% in the LR group and 97.6% in the HR group. Plasma levels of arsenic remained stable after the administration of RIF at a dosage of 60 mg/kg/d for seven days and returned to baseline levels within fourteen days after discontinuation of RIF administration, which is consistent with a concentration of 135 mg/d/kg. Furthermore, controlling white blood cells (WBC) to maintain levels at or below 30 × 10⁹/L during induction therapy can decrease the incidence of induced differentiation syndrome (DS) or alleviate its symptoms. Our study demonstrated that the CCCG-APL-2017 protocol, which combines RIF with ATRA, is both effective and safe in treating children with APL.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"30 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901583","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":"Piezo1-mediated mechanotransduction regulates the translational activity, function and lung pathogenicity of group 2 innate lymphoid cells","authors":"MinYeong Lim, Seonjun Park, Yoon Ha Joo, Sung Eun Kim, Min Hee Ham, TaeSoo Kim, Kihyuck Kwak, Sung Joon Kim, Jung Chan Lee, Sung Ho Park, Hye Young Kim","doi":"10.1038/s41392-025-02350-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02350-4","url":null,"abstract":"<p>Group 2 innate lymphoid cells (ILC2s) are central effectors of type 2 immune responses in the lung; however, how mechanical cues regulate their function remains unclear. Here, we identified the mechanosensitive ion channel Piezo1 as a key regulator of ILC2 effector function through translational control. Piezo1 is highly expressed in murine and human ILC2s, and its activation by mechanical stress or the Piezo1 agonist, Yoda1 induces calcium influx, triggering mTOR signaling and selectively enhancing IL-13 protein production. Conditional deletion of Piezo1 in ILC2s reduced mTOR activation and puromycin incorporation, leading to impaired protein synthesis and attenuated lung inflammation and fibrosis in the IL-33, <i>Alternaria alternata</i>, and bleomycin models. scRNA-seq and scATAC-seq confirmed that Piezo1-deficient ILC2s retained <i>Il13</i> transcription and chromatin accessibility but presented translational suppression, as evidenced by protein‒mRNA interactions. Pharmacologic mTOR inhibition phenocopied Piezo1 loss, supporting the functional relevance of the Piezo1–mTOR axis. These findings demonstrate that Piezo1 functions as a mechanosensor that integrates biomechanical cues to regulate cytokine output via mTOR-mediated translation. Targeting Piezo1 signaling or its downstream effectors may provide therapeutic benefits in type 2 inflammation–associated lung diseases.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"49 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899068","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":"First-line tislelizumab and ociperlimab combined with gemcitabine and cisplatin in advanced biliary tract cancer (ZSAB-TOP): a multicenter, single-arm, phase 2 study","authors":"Guoming Shi, Xiaoyong Huang, Liang Ma, Hui Li, Jianhong Zhong, Junye Wang, Qiang Gao, Xiaojun Guo, Shuangjian Qiu, Huichuan Sun, Yinghong Shi, Xiaowu Huang, Xiaoying Wang, Yong Yi, Xiaodong Zhu, Cheng Huang, Zhenbin Ding, Yi Chen, Yifeng He, Yinghao Shen, Qiman Sun, Jian Zhou, Jia Fan","doi":"10.1038/s41392-025-02356-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02356-y","url":null,"abstract":"<p>Adding a PD-1/PD-L1 inhibitor to gemcitabine plus cisplatin (GemCis) has shown survival benefits in advanced biliary tract cancer (BTC). Dual inhibition of PD-1/PD-L1 and TIGIT may act synergistically, and further enhance antitumor effects. ZSAB-TOP was a single-arm, multicenter, phase 2 study (NCT05023109) evaluating efficacy and safety of first-line tislelizumab (a PD-1 inhibitor) plus ociperlimab (a TIGIT inhibitor) and GemCis in advanced BTC. Eligible patients received tislelizumab (200 mg) and ociperlimab (900 mg) on day 1 until unacceptable toxicity or disease progression, in combination with cisplatin (25 mg/m²) and gemcitabine (1000 mg/m²) on days 1 and 8 of a 21-day cycle for a maximum eight cycles. The primary endpoint was confirmed objective response rate (ORR) evaluated by the investigator, which was compared with a historical ORR of 25% with GemCis, with a statistical superiority setting at p ≤ 0.05. From March 8, 2022, to January 18, 2023, 45 patients were enrolled. Among the 41 patients in the efficacy analysis set, the confirmed ORR was 51.2% (95% CI 35.1–67.1), achieving the statistical superiority criteria (p = 0.0003). Patients who had TIGIT⁺/PD-L1⁺ (n = 16) tended to have a numerically greater confirmed ORR (75.0% [95% CI 47.6–92.7]). After a median follow-up of 14.6 months, median progression-free survival was 7.7 months (95% CI 6.0–9.4), with a median overall survival of 17.4 months (95% CI 11.7-not reached). Treatment-related adverse events of grade ≥3 occurred in 60.0% of patients; immune-mediated adverse events of any grade was observed in 42.2%, with the majority being grade 1 or 2. In conclusion, first-line tislelizumab and ociperlimab plus GemCis yielded clinically promising tumor response and survival outcomes in advanced BTC and were generally well tolerated without new safety signals.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"8 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899076","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":"Fencing the genome: ubiquitin signaling restricts heterochromatin spread","authors":"Collin Bakker, Joanna Paulson, Nitika Taneja","doi":"10.1038/s41392-025-02349-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02349-x","url":null,"abstract":"<p>In a recent study published in <i>Science</i>, Tiebang Kang and his colleagues¹ identify ASB7 as a key negative regulator of heterochromatin maintenance through targeted degradation of the H3K9me3 methyltransferase SUV39H1. The work uncovers a cell cycle-regulated chromatin-associated ubiquitin ligase circuit that maintains epigenetic homeostasis and reveals a novel vulnerability in cancer that may be exploited therapeutically.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"13 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144899111","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":"F-box/LRR-repeat protein 12 reorchestrated microglia to inhibit scarring and achieve adult spinal cord injury repair.","authors":"Xu Xu, Feng Gao, Qixin Chen, Bairu Chen, Wenyu Liang, Runzhi Huang, Yuchen Liu, Zhibo Liu, Yanjing Zhu, Gufa Lin, Bei Ma, Letao Yang, Shaorong Gao, Rongrong Zhu, Liming Cheng","doi":"10.1038/s41392-025-02354-0","DOIUrl":"10.1038/s41392-025-02354-0","url":null,"abstract":"<p><p>Scarring is an insurmountable obstacle for axonal regeneration in recovery from spinal cord injury (SCI). It impedes the repair effects of therapeutic targets in cortical neurons, such as PTEN^-/- and hyper-IL-6, which cannot break through dense scar barriers to reconstruct neural circuits. However, methods for eliminating this process remain elusive. Here, we conducted a multiomics analysis of SCI and identified FBXL12 as an effective target for inhibiting scarring, further promoting spontaneous crossing of axons at the epicenter. We identified N6-Methyladenosine (m6A) modification as the predominant mRNA modification in SCI, with Fbxl12 being a major modification target. Furthermore, m6A modification specifically promoted FBXL12 synthesis in activated microglia. The overexpression of FBXL12 in microglia contributed to its homogeneous distribution and maintained a \"scar-less healing\" phenotype. Remarkably, FBXL12 therapy effectively reduced extracellular matrix deposition and decreased the scar area by ~70%. Importantly, axons grew through the epicenter and reached a length of more than 2.4 mm 56 days post-SCI, significantly improving motor function and reconstructing the neural circuit. Mechanistically, FBXL12 promoted cytoskeletal reorganization and migration in microglia by catalyzing the K63-linked ubiquitylation of Myosin heavy chain 14 (MYH14). Together, our results identify m6A-FBXL12-MYH14 axis as a novel cytoskeletal reorganization pathway in activated microglia and suggest FBXL12 as an effective target for a novel microglia-based approach to facilitate scarless functional recovery in SCI.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":"259"},"PeriodicalIF":52.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12365319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883588","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}

{"title":"NADPH oxidase 1/4 dual inhibition impairs transforming growth factor-beta protumorigenic effects in cholangiocarcinoma cancer-associated fibroblasts.","authors":"Josep Amengual, Ester Gonzalez-Sanchez, Mariana Yáñez-Bartolome, Laura Sererols-Viñas, Aashreya Ravichandra, Celia Guiton, Noel P Fuste, Ania Alay, Sara Hijazo-Pechero, Beatriz Martín-Mur, Marta Gut, Anna Esteve-Codina, Ana Cantos-Cortes, Rut Espinosa-Sotelo, Emilio Ramos, Teresa Serrano, Mariona Calvo, Berta Laquente, Joana Ferrer, Gabriel Pons, Andrés Mendez-Lucas, Steven Dooley, Sumera I Ilyas, Marie Vallette, Lynda Aoudjehane, Marie Lequoy, Laura Fouassier, Cédric Coulouarn, Silvia Affò, Alexander Scheiter, Diego F Calvisi, Tian V Tian, Isabel Fabregat, Javier Vaquero","doi":"10.1038/s41392-025-02347-z","DOIUrl":"10.1038/s41392-025-02347-z","url":null,"abstract":"<p><p>Transforming growth factor beta (TGF-β) signalling has become an attractive therapeutic target due to its pro-tumorigenic actions on epithelial cells and its immunosuppressive effects in the tumour microenvironment. In intrahepatic cholangiocarcinoma (iCCA), a highly aggressive malignancy of the biliary tract with poor prognosis, the latest clinical trials using TGF-β inhibitors have failed indicating that the specific actions carried out by TGF-β in iCCA are yet not well delineated. Here, we show that TGF-β signalling is highly active in iCCA and exerts a prominent suppressor effect on tumour cell lines and organoids established from iCCA metastases biopsies, that relies on a functional canonical SMAD2/3/4 signalling. Thus, TGF-β inhibitors promote, instead of inhibiting, tumour cell growth. In this context, a promising strategy is to target intracellular proteins downstream the TGF-β receptors accounting only for TGF-β pro-tumorigenic actions. NADPH oxidase 4 (NOX4), a downstream mediator of the TGF-β signalling pathway, is strictly expressed in cancer-associated fibroblasts (CAF) of iCCA and acts in concert with NOX1 to regulate CAF functions. Use of a dual NOX4/NOX1 inhibitor impaired CAF actions and reduced tumour growth in vitro and in two different in vivo iCCA experimental models. Collectively, our findings reveal an actionable way to specifically target TGF-β pro-tumorigenic actions in CAF from iCCA without undesirable side effects on tumour cells, suggesting a potentially bright future for dual NOX4/NOX1 inhibitors in the clinics, alone or in combination with other therapies.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":"257"},"PeriodicalIF":52.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12358586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144875072","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}

{"title":"DNA/RNA-binding protein KIN17 supports esophageal cancer progression via resolving noncanonical STING activation induced by R-loop.","authors":"Zichao Wei,Ning Zhao,Lu Kuang,Ji Cong,Sujuan Zheng,Yi Li,Zhihua Liu","doi":"10.1038/s41392-025-02344-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02344-2","url":null,"abstract":"Targeting the DNA damage response (DDR) exhibits potent efficacy in inducing immune activation and enhancing patient prognosis. However, the benefits of DDR regulation are not universally observed across all patients, owing to the intricate compensatory mechanisms operative in certain cancers. There still exists a gap in the function of activated DDR protein in esophageal squamous cell carcinoma (ESCC). Here, we demonstrate that increased expression of DDR genes contributes to the progression of esophageal squamous cell carcinoma and suppresses the tumor immune microenvironment. Notably, the abundant presence of the DDR protein KIN in ESCC tissues facilitates efficient DNA damage clearance and promotes escape from apoptosis. Depletion of KIN significantly inhibited proliferation and induced DNA damage accumulation in ESCC cells. Mechanistically, KIN functions to support the recruitment of the R-loop regulator DHX9 to R-loop sites, thereby addressing DNA damage associated R-loops. Intriguingly, the depletion of KIN activates the STING pathway via NFκB signaling, which is induced by the accumulation of R-loops, ultimately initiating an innate immune response. Depletion of KIN improved the immune microenvironment and the effect of immune therapy in mouse model. Collectively, our findings identify KIN as a novel R-loop binding protein that facilitates the recruitment of the R-loop resolution complex and suppresses tumor-intrinsic innate immunity.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"96 1","pages":"256"},"PeriodicalIF":39.3,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144850777","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}