Signal Transduction and Targeted Therapy最新文献

{"title":"Immune regulation includes an effector arm: therapeutic implications of phase III IDO/PD-L1 vaccination in melanoma.","authors":"Mads Hald Andersen","doi":"10.1038/s41392-026-02993-x","DOIUrl":"10.1038/s41392-026-02993-x","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13588775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002414","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":"Chromosomal instability in cancer: sources, consequences and new therapeutic opportunities.","authors":"Angela Flavia Serpico, Domenico Grieco","doi":"10.1038/s41392-026-02940-w","DOIUrl":"10.1038/s41392-026-02940-w","url":null,"abstract":"<p><p>Chromosomal instability (CIN) refers to a high rate of chromosome segregation errors during consecutive cell divisions and is a hallmark of cancers with aggressive behavior and poor prognosis. Cancer cells exhibiting CIN may acquire both numerical (N-CIN) and structural (S-CIN) chromosome alterations, namely by chromosome mis-segregation and DNA replication/repair defects, respectively. Importantly, these processes are tightly interconnected: mis-segregating chromosomes are prone to DNA damage, while DNA replication or repair defects can, in turn, promote chromosome mis-segregation. Consequently, CIN emerges as a consequence of these intertwined occurrences. CIN can confer survival advantages to cancer cells by enhancing their adaptation abilities, promoting intratumor heterogeneity, therapy resistance and acquisition of metastatic potential. In contrast, induction of CIN in healthy cells typically compromises cellular fitness and viability, triggering senescence and apoptosis. Therefore, cancer cells develop specific adaptation capabilities that allow them to tolerate CIN, often becoming dependent on specific CIN tolerance pathways. Elucidating the molecular circuits underlying CIN and clarifying the basis of its multifaceted roles in cancer will deepen our understanding of tumorigenesis and reveal therapeutically exploitable vulnerabilities in chromosomally unstable cancers. Here, we provide an integrated perspective on the principal sources of CIN, newly identified CIN-specific dependencies and vulnerabilities and how CIN impacts genome integrity. We discuss emerging evidence on the potential influence of CIN on tumor evolution or regression, including the CIN paradox. We further highlight how integrating this novel information with emerging diagnostic technologies that allow quantitative, qualitative and spatiotemporal characterization of CIN within tumors is reshaping our ability to define CIN at the single-tumor level, opening new avenues for targeted therapeutic strategies.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13588816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002436","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":"An integrated multiomic single-vesicle atlas delineates graft exosome heterogeneity in chronic lung allograft dysfunction.","authors":"Dong Tian, Xiangyun Zheng, Zengwei Yu, Dapeng Wang, Weiyang Chen, Yaling Liu, Zehui Liu, Boyang Xia, Xiaohan Jin, Haoji Yan, Ye Wu, Yongsheng Zhao, Chuanfen Zhang, Qiang Pu, Jingyu Chen, Masaaki Sato, Lunxu Liu","doi":"10.1038/s41392-026-02927-7","DOIUrl":"10.1038/s41392-026-02927-7","url":null,"abstract":"<p><p>The underlying mechanisms of exosomes in chronic lung allograft dysfunction (CLAD) remain poorly understood. The primary challenge lies in the substantial functional heterogeneity of exosomes in CLAD. In this study, lung transplantation was initially performed, followed by the generation of a chronic rejection (CR) model in rats to simulate CLAD in humans. Exosomes from lung graft tissues were extracted, purified, and subjected to proximity barcoding assay-based single-vesicle membrane proteomic profiling. Additionally, bulk proteomic and metabolomic profiling of the graft tissues was conducted. Exosomes were categorized into 14 clusters. Compared with the syngeneic group, the CR group had significantly lower levels of clusters 7 (Nphs1^high), 13 (Aqp1^high), and 14 (Csf3r^high), and higher levels of clusters 2 (Lrp2^high Mrc1^high) and 4 (Nt5e^high). The abundance of cluster 12 (Ilk^high) exosomes was strongly correlated with pleural thickness (r = -0.90, P < 0.001). Cluster 12 exosomes exhibited the greatest number of related differentially expressed proteins and metabolites. The proteins correlated with cluster 12 were enriched in the \"complement and coagulation cascades\", whereas the metabolites were enriched in the \"glycerophospholipid metabolism\". Further verification in patients with restrictive allograft syndrome revealed the same decrease in abundance of cluster 12 exosomes as that observed in the rat model. Finally, the core molecular network of cluster 12 that contributes to pleural thickening in CLAD was constructed. In this study, the heterogeneous composition of exosomes in lung grafts was mapped to expand the understanding of their effects and to drive their application in CLAD.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13588815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149002428","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":"Targeting super elongation complex-driven RNA polymerase II elongation reduces plaque vulnerability.","authors":"Karoline E Kokot, Sebastian Reichardt, Christian Menedo, Stephan Erbe, Jasmin M Kneuer, Kaylin C A Palm, Julian Hoba, Michael Andritschke, Mirko Katzmann, Annika Reuser, Moritz von Scheidt, Michal Mokry, Junjie Xiao, Bilal N Sheikh, Nora Klöting, Ulrich Laufs, Jes-Niels Boeckel","doi":"10.1038/s41392-026-02962-4","DOIUrl":"10.1038/s41392-026-02962-4","url":null,"abstract":"<p><p>Atherosclerotic plaque rupture is a major cause of myocardial infarction and stroke, yet the mechanisms governing plaque stability remain incompletely understood. Endothelial activation can trigger endothelial-to-mesenchymal transition, a program linked to endothelial dysfunction and lesion vulnerability. Here we investigated whether transcriptional pause release and RNA polymerase II elongation constitute an early regulatory layer that promotes endothelial-to-mesenchymal transition and atherosclerosis. Analysis of human plaque single-cell transcriptomics indicated increased expression of super elongation complex components in endothelial cells with a transition signature. In primary human endothelial cell models, pharmacological inhibition of the super elongation complex attenuated the induction of mesenchymal markers. AFF4, pCDK9, and pSMAD2/3 showed physical interaction during endothelial transition. Genome-wide profiling of RNA polymerase II occupancy revealed reduced promoter-proximal pausing during early transition, accompanied by a rapid increase in nascent transcriptional elongation rates. Super elongation complex inhibition restored pausing and suppressed fast-responding transition-associated target genes. In a human cardiac organoid model, inhibition of the super elongation complex prevented EndMT-induced fibrillar collagen deposition and prevented the loss of beating rate. In a hyperlipidemic Pcsk9 gain-of-function mouse model, super elongation complex inhibition administered both prophylactically and therapeutically after established atherosclerosis reduced plaque burden and reduced features of plaque vulnerability. Finally, analysis of 1048 human plaque segments from the Athero-Express biobank showed significant associations between the elongation axis and multiple vulnerability-related plaque traits. Together, these findings identify rapid transcriptional elongation as a mechanistic driver of endothelial plasticity and features of plaque vulnerability and support targeting the elongation machinery as a potential strategy to reduce features of plaque vulnerability in atherosclerotic disease.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13583046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983623","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":"Mechanical load as an endogenous tumor suppressor: Nesprin-2-mediated mechanotransduction reshapes the cancer epigenome.","authors":"Kostas A Papavassiliou, Athanasios G Papavassiliou","doi":"10.1038/s41392-026-02973-1","DOIUrl":"10.1038/s41392-026-02973-1","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13578746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977919","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":"SCF^JFK regulates osteoblast differentiation through targeting RUNX2.","authors":"Zesen Shang, Yue Zhang, Yang Liu, Xinyi Yuan, Jichuang Wang, Dongwei Fan, Da Zou, Dazhao Tie, Fei Pei, Hongshan Zhao, Shuguo Zheng, Xinjing Tang, Weishi Li, Lin He","doi":"10.1038/s41392-026-02837-8","DOIUrl":"10.1038/s41392-026-02837-8","url":null,"abstract":"<p><p>RUNX2 (Runt-related transcription factor 2) is a master regulator of osteogenesis, and its genetic mutations are associated with ~65% cases of cleidocranial dysplasia (CCD), an autosomal dominant abnormal bone development disorder in humans with defective intramembranous bone formation. However, how these mutations affect bone formation remains to be investigated. Here, we report that RUNX2 interacts with the F-box protein JFK and is destabilized by the SKP1-CUL1-JFK E3 ubiquitin ligase complex (SCF^JFK). We find that several CCD-associated mutations of RUNX2 acquire an increased affinity toward SCF^JFK thus an accelerated proteasomal degradation. We demonstrate that SCF^JFK-mediated RUNX2 degradation suppresses osteoblast differentiation. Consistently, Jfk-null mice exhibit increased trabecular bone volume and bone mineral density and are resistant to Runx2 haploinsufficiency-induced CCD-like syndrome. Interestingly, RUNX2 binds to the JFK promoter and represses its transcription, establishing a feedback loop to promote osteoblast differentiation, and remarkably, the CCD-associated RUNX2 mutants also display an impaired transcription repression of JFK. Our study demonstrates SCF^JFK as an E3 ligase for RUNX2 and uncovers a feedback regulatory loop between SCF^JFK and RUNX2 that is implemented in bone development and implicated in CCD, supporting the pursuit of JFK as a potential target to ameliorate CCD-like syndrome.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13582849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983698","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":"HIF1α-KLF4 signaling dictates extra-erythrocyte expression of hemoglobin conferring sorafenib resistance in hepatocellular carcinoma.","authors":"Bo Zhang, Feichang Liu, Xinyue Gao, Yichao Zhu, Tong Chen, Jiahui Hao, Yuexian Wei, Zhuoran Sun, Ruigang Yang, Yalan Yang, He Ren, Yutong Li, Chunxiao Yu, Tianyi Ren, Yinuo Huang, Hong Jiang, Gerry Melino, Li Ma, Hongyan Huang, Qiang Sun","doi":"10.1038/s41392-026-02971-3","DOIUrl":"10.1038/s41392-026-02971-3","url":null,"abstract":"<p><p>Cancer cells must deal with excessive reactive oxygen species (ROS) to survive severe hypoxia and anticancer therapy; however, anti-ROS mechanisms other than the well-known NFE2L2/NRF2 signaling pathway are poorly recognized. Here, we report a ROS scavenging mechanism mediated by HIF1α-KLF4-induced hemoglobin extraerythrocytically expressed in hepatocellular carcinoma (HCC). We found that the ROS pathway was aberrantly activated in HCC and was associated with hemoglobin upregulation, which independently predicts poor outcomes. Network analysis further identified heme binding as the top ROS-associated functional module, suggesting a previously unrecognized role of hemoglobin in maintaining redox homeostasis in HCC. Hemoglobin expression in cancer cells is transcriptionally controlled by HIF1α via KLF4 but not HIF2α or the recently identified KDM5A-KLF1 signaling. The upregulated hemoglobin counteracts the detrimental effects of oxidative stress by scavenging ROS, promoting sorafenib resistance, which could be effectively reversed by interfering with hemoglobin expression, leading to tumor suppression. Both in vitro and in vivo experiments consistently supported the functional importance of hemoglobin in regulating oxidative stress adaptation and therapeutic response. Overall, a previously unrecognized mechanism was identified for cancer cell survival under oxidative stress, where HIF1α-KLF4 signaling induces hemoglobin to scavenge ROS produced during hypoxia and anticancer therapy, providing a promising target of synthetic lethality for cancer therapeutics.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13578305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148977881","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":"The histone deacetylase family in health and disease.","authors":"Ri Wen, Yu-Hang Yang, Tao Zhang, Sen-Yu Zhang, Xin-Ru Yang, Li-Ying Zhang, Peng-Hui Hao, Yue Zheng, Ni Yang, Tie-Ning Zhang","doi":"10.1038/s41392-026-02764-8","DOIUrl":"10.1038/s41392-026-02764-8","url":null,"abstract":"<p><p>Zinc-dependent classical histone deacetylases, including Classes I, II, and IV, are ubiquitously present in mammals and play vital roles in numerous biological processes. To date, eleven histone deacetylase members have been identified, namely, histone deacetylase 1 through histone deacetylase 11. A growing body of evidence underscores the crucial roles of these histone deacetylase members in both physiological and pathological conditions. Notably, these histone deacetylase members are involved in various cellular processes, including inflammation, metabolism, apoptosis, and oxidative stress. Consequently, histone deacetylases have emerged as promising therapeutic targets for a range of pathological conditions, including tumors, cardiovascular diseases, and neurological disorders. Moreover, the development of histone deacetylase modulators, which can regulate their activity, has shown significant therapeutic potential across various conditions. Several histone deacetylase inhibitors have been approved by the U.S. Food and Drug Administration for the treatment of multiple tumors and Duchenne muscular dystrophy, while many others are being developed for oncology and other therapeutic applications. In this review, we introduce the research history and structural characteristics of histone deacetylases. We then summarize the molecular mechanisms and biological functions of the eleven histone deacetylase family members. Moreover, we elucidate the critical regulatory roles of histone deacetylases in various human diseases. Furthermore, we provide an overview of histone deacetylase modulators, their current clinical applications, and potential benefits, offering insight into the regulation of histone deacetylases for the treatment of related diseases.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148971131","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":"Hepassocin prevents age-related liver senescence and facilitates liver regeneration by activating AMPK.","authors":"Yang Yang, Hui Chen, Shensi Xiang, Yujia Wei, Limin Zhang, Aihua Sun, Xiao E, Fan Wu, Ning Luo, Fei Liang, Xiaojie Wu, Chenyu Wang, Zhuo Chen, Qizheng Zhang, Xinrui Chen, Qinlu Wu, Zixuan Han, Changyan Li, Ronghua Yin, Guangming Ren, Jingjing Li, Ke Zhao, Huiying Gao, Ruijia Wang, Miao Yu, Xiaoming Yang","doi":"10.1038/s41392-026-02773-7","DOIUrl":"10.1038/s41392-026-02773-7","url":null,"abstract":"<p><p>Liver aging significantly impairs hepatic function and regenerative capacity, increasing the risk of morbidity and mortality from chronic liver diseases. Identifying molecular regulators of these processes may reveal promising therapeutic targets. Although Hepassocin (HPS), a hepatokine with known hepatoprotective functions, has minimal effects on liver homeostasis in adult mice, its role in long-term liver maintenance remains unclear. In this study, we observed a decrease in circulating and intrahepatic HPS levels in both aged mice and elderly humans. Moreover, the upregulation of HPS following two-thirds partial hepatectomy (PHx) was significantly blunted in 12-month-old (aged) mice. Aged HPS-knockout (KO) mice exhibited variable hepatic steatosis, exacerbated cellular senescence, and impaired autophagy. Liver regeneration after PHx was severely compromised in aged HPS-KO mice, as indicated by increased mortality, reduced hepatocyte proliferation, delayed liver mass recovery, and worsened autophagy disruption. Mechanistically, HPS directly activated 5'-AMP-activated protein kinase catalytic subunit alpha-1 (AMPK) in hepatocytes via the Annexin A2 (ANXA2)-extracellular signal-regulated kinase 2-90 kDa ribosomal protein S6 kinase 1-liver kinase B1 (ANXA2-ERK-p90RSK-LKB1) signaling cascade. Compared with their wild-type littermates, aged HPS-KO mice presented reduced LKB1 and AMPK activation and elevated mechanistic target of rapamycin kinase (mTOR) activity in both quiescent and regenerating livers. Treatment with the AMPK agonist AICAR ameliorated the liver aging phenotype and restored liver regenerative capacity in aged HPS-KO mice. Importantly, the administration of exogenous HPS enhanced regenerative outcomes in aged wild-type mice. These results establish HPS as a novel protective factor against liver senescence through AMPK-dependent mechanisms. Therapeutic strategies aimed at enhancing HPS signaling may offer a viable approach to counteract age-related liver dysfunction and regeneration failure.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148971141","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":"Interleukin-1 receptor-associated kinase 1 controls chemoresistance and immuno-killing in non-small cell lung cancer.","authors":"Sabrina Digiovanni, Claudia Giannotta, Luca Alessandri, Simona Fontana, Angelo Meoli, Paolo Bironzo, Alessandra Merlini, Gabriella Doronzo, Parab Sushant, Elisa Balmas, Muhlis Akman, Joanna Kopecka, Maddalena Arigoni, Francesca Napoli, Julia Wens, Samuele Tarallo, Alessandro Bertero, Stefano Guglielmo, Barbara Rolando, Davide Palma, Luisella Righi, Massimo Massaia, Raffaele Calogero, Federico Bussolino, Silvia Novello, Giorgio Vittorio Scagliotti, Iris Chiara Salaroglio, Chiara Riganti","doi":"10.1038/s41392-026-02848-5","DOIUrl":"10.1038/s41392-026-02848-5","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) shows partial chemoimmunoresistance, driven by the upregulation of the drug efflux transporters ABCB1 and ABCC1 and the downregulation of the immunosensitizer protein ABCA1. To elucidate the molecular mechanisms underlying this chemoimmunoresistant phenotype, by performing a CRISPR-KO kinome screening, we identified interleukin-1 receptor-associated kinase 1 (IRAK1) as a key determinant of chemoimmunosensitive and chemoimmunoresistant phenotypes, defined as ABCB1/ABCC1^lowABCA1^high and ABCB1/ABCC1^highABCA1^low, respectively. IRAK1 expression was significantly associated with poor prognosis in the TCGA-LUAD cohort and in early-stage NSCLC patients. The IRAK1/ABCB1/ABCC1^highABCA1^low signature was predictive of poor response to chemotherapy and immunotherapy in advanced-stage patients. Mechanistically, IRAK1 silencing resensitized NSCLC cells to cisplatin by decreasing IL-1R/NFκB and IL-1R/AP-1 signaling, which in turn downregulated the drug efflux transporters ABCB1 and ABCC1. Concurrently, IRAK1 silencing activated the LXRα/ABCA1 axis, which enhanced Vγ9Vδ2 Tcell-mediated cytotoxicity and facilitated the recruitment of memory and effector CD4⁺ and CD8⁺ T cells in both ex vivo autologous cocultures and immunoxenografts, increasing the immuno-killing ability of tumor cells. Newly developed synthetic inhibitors of IRAK1 efficiently promoted chemo- and immunosensitization in immunoxenografts, resulting in good pharmacokinetic and safety profiles. These findings identify IRAK1 as a novel, druggable target that controls both chemoresistance and immune evasion in NSCLC. We suggest the pharmacological inhibition of IRAK1 as a future promising strategy to overcome resistance to chemotherapy and improve patient outcomes.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":81.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13575119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148971119","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}