Pub Date : 2026-02-11DOI: 10.1038/s41388-026-03679-y
Xinxin Li, Shuangmei Liu, Ruoyu Wang, Xinlei Wang
Non-small cell lung cancer (NSCLC) with spinal metastasis represents a clinical challenge due to its aggressive nature, limited treatment options, and profound impact on patient quality of life. Here, we report the development of an innovative upconversion mesoporous silica nanoparticle (UCMS) platform co-loaded with celecoxib and rose bengal (UCMS@CXB/RB), engineered to synergistically combine photodynamic therapy (PDT) and cyclooxygenase-2 (COX-2) inhibition. Upon near-infrared (NIR) irradiation, UCMS@CXB/RB generated abundant reactive oxygen species, triggered immunogenic cell death, and significantly suppressed prostaglandin E2 signaling, leading to reduced angiogenesis and improved antitumor immunity. In vitro and in vivo studies confirmed that this nanoplatform effectively remodeled the tumor microenvironment, inhibited tumor growth, and alleviated cancer-induced spinal dysfunction. Single-cell multi-omics analysis further revealed dynamic crosstalk among immune cells, tumor cells, and endothelial populations, providing mechanistic insights into the multifaceted therapeutic effects of UCMS@CXB/RB. Our results underscore the clinical potential of integrating PDT with targeted COX-2 blockade to address the complex pathophysiology of NSCLC spinal metastasis. This study presents a promising minimally invasive therapeutic strategy with strong translational relevance for managing metastatic NSCLC and improving patient outcomes.
{"title":"Upconversion mesoporous silica nanoparticles co-delivering celecoxib and rose bengal enable multimodal immunogenic and anti-angiogenic therapy for spinal metastasis of non-small cell lung cancer","authors":"Xinxin Li, Shuangmei Liu, Ruoyu Wang, Xinlei Wang","doi":"10.1038/s41388-026-03679-y","DOIUrl":"10.1038/s41388-026-03679-y","url":null,"abstract":"Non-small cell lung cancer (NSCLC) with spinal metastasis represents a clinical challenge due to its aggressive nature, limited treatment options, and profound impact on patient quality of life. Here, we report the development of an innovative upconversion mesoporous silica nanoparticle (UCMS) platform co-loaded with celecoxib and rose bengal (UCMS@CXB/RB), engineered to synergistically combine photodynamic therapy (PDT) and cyclooxygenase-2 (COX-2) inhibition. Upon near-infrared (NIR) irradiation, UCMS@CXB/RB generated abundant reactive oxygen species, triggered immunogenic cell death, and significantly suppressed prostaglandin E2 signaling, leading to reduced angiogenesis and improved antitumor immunity. In vitro and in vivo studies confirmed that this nanoplatform effectively remodeled the tumor microenvironment, inhibited tumor growth, and alleviated cancer-induced spinal dysfunction. Single-cell multi-omics analysis further revealed dynamic crosstalk among immune cells, tumor cells, and endothelial populations, providing mechanistic insights into the multifaceted therapeutic effects of UCMS@CXB/RB. Our results underscore the clinical potential of integrating PDT with targeted COX-2 blockade to address the complex pathophysiology of NSCLC spinal metastasis. This study presents a promising minimally invasive therapeutic strategy with strong translational relevance for managing metastatic NSCLC and improving patient outcomes.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 9","pages":"823-839"},"PeriodicalIF":7.3,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165711","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}
Cuproptosis is involved in the proliferation, metastasis, and drug resistance formation development of renal cell carcinoma (RCC) by regulating lipid metabolism and oxidative stress levels in the tumor microenvironment, with Ferredoxin 1 (FDX1) as a core regulator. Proline-rich 15 (PRR15) is a proline-rich protein, that we previously found to inhibit the malignant progression of triple-negative breast cancer through the regulation of the phosphatidylinositol 3-kinase (PI3K) pathway and epithelial-mesenchymal transition (EMT) pathway. However, the role of PRR15 in cuproptosis and its molecular mechanisms remain unknown. This study found confirmed that PRR15 promotes cuproptosis and mitochondrial damage in RCC cells and inhibits tumor proliferation and metastasis, as demonstrated in vivo and in vitro. When RCC develops, PRR15 silencing activates the nuclear factor kappa-B (NF-κB) signaling pathway, which inhibits FDX1 expression, ultimately blocking the cuproptosis process and increasing tumor invasiveness. Conversely, overexpression of PRR15 reverses this phenotype. This study reveals for the first time the regulatory mechanism of the PRR15/NF-κB/FDX1 axis in cuproptosis in RCC, providing a new strategy for the treatment of RCC patients.
cuprotosis通过调节肿瘤微环境中的脂质代谢和氧化应激水平，参与肾细胞癌（RCC）的增殖、转移和耐药形成发展，其中铁氧化还蛋白1 （FDX1）是核心调控因子。Proline-rich 15 （PRR15）是一种富含脯氨酸的蛋白，我们之前发现它通过调节磷脂酰肌醇3-激酶（PI3K）途径和上皮-间质转化（EMT）途径抑制三阴性乳腺癌的恶性进展。然而，PRR15在铜突起中的作用及其分子机制尚不清楚。本研究在体内和体外均证实了PRR15促进RCC细胞铜增生和线粒体损伤，抑制肿瘤增殖和转移的作用。当RCC发生时，PRR15沉默激活核因子κ b （NF-κB）信号通路，抑制FDX1的表达，最终阻断cuprosis过程，增加肿瘤侵袭性。相反，PRR15的过表达会逆转这种表型。本研究首次揭示了PRR15/NF-κB/FDX1轴在RCC铜质增生中的调控机制，为RCC患者的治疗提供了新的策略。
{"title":"PRR15 suppresses renal cell carcinoma progression via the NF-κB/FDX1 axis to induce cuproptosis and mitochondrial dysfunction","authors":"Jialu Ma, Jianqiao Li, Zhihao Bo, Shiyue Zhang, Yuankang Feng, Xinyu Liu, Yihan Dong, Jiaxin Li, Shaomin Guo, Yuejing Pan, Huamao Jiang, Rui Wang, Dan Yue, Yong Wang","doi":"10.1038/s41388-026-03683-2","DOIUrl":"10.1038/s41388-026-03683-2","url":null,"abstract":"Cuproptosis is involved in the proliferation, metastasis, and drug resistance formation development of renal cell carcinoma (RCC) by regulating lipid metabolism and oxidative stress levels in the tumor microenvironment, with Ferredoxin 1 (FDX1) as a core regulator. Proline-rich 15 (PRR15) is a proline-rich protein, that we previously found to inhibit the malignant progression of triple-negative breast cancer through the regulation of the phosphatidylinositol 3-kinase (PI3K) pathway and epithelial-mesenchymal transition (EMT) pathway. However, the role of PRR15 in cuproptosis and its molecular mechanisms remain unknown. This study found confirmed that PRR15 promotes cuproptosis and mitochondrial damage in RCC cells and inhibits tumor proliferation and metastasis, as demonstrated in vivo and in vitro. When RCC develops, PRR15 silencing activates the nuclear factor kappa-B (NF-κB) signaling pathway, which inhibits FDX1 expression, ultimately blocking the cuproptosis process and increasing tumor invasiveness. Conversely, overexpression of PRR15 reverses this phenotype. This study reveals for the first time the regulatory mechanism of the PRR15/NF-κB/FDX1 axis in cuproptosis in RCC, providing a new strategy for the treatment of RCC patients.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 9","pages":"840-855"},"PeriodicalIF":7.3,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-11DOI: 10.1038/s41388-026-03685-0
Xiaoya Zhao, Long Gao, Ran Chen, Hanchen Tian, Shuangshuang Liang, Zhuofan Zhang, Wenjie Li, Jingshuai Sun, Xuemei Chen, Xiaoyu Tang, Tian Lan, Yuan Sun, Jingyun Ma
Stimulator of interferon genes (STING) agonists have shown promise in cancer immunotherapy by enhancing type I interferon (IFN-I) signaling. However, the antiviral effects of IFN-I can suppress viral replication, limiting their combination with oncolytic viruses. This study demonstrates that combining a naturally isolated Senecavirus A (SVA) strain with the STING agonist MSA-2 supports synergistic IFN-I activation across multiple tumor models. The combination induces robust innate and adaptive antitumor immune responses without impairing SVA replication. Transcriptomics, immunoblotting and early IRF7 nuclear translocation in B16‑F10 cells are consistent with engagement of the RIG‑I/MDA5–TBK1–IRF7 axis. In vivo, co‑treatment enhanced IFN‑β induction, increased CD8⁺ T‑cell infiltration and reduced tumor burden relative to monotherapies, whereas efficacy was not observed in athymic nude mice, supporting T‑cell dependence. Together, these data provide preclinical evidence that a rational oncolytic virus and STING combination can amplify antitumor immunity without overtly compromising viral persistence.
{"title":"Synergistic reprogramming of the tumor immune microenvironment by Senecavirus A and STING agonist","authors":"Xiaoya Zhao, Long Gao, Ran Chen, Hanchen Tian, Shuangshuang Liang, Zhuofan Zhang, Wenjie Li, Jingshuai Sun, Xuemei Chen, Xiaoyu Tang, Tian Lan, Yuan Sun, Jingyun Ma","doi":"10.1038/s41388-026-03685-0","DOIUrl":"10.1038/s41388-026-03685-0","url":null,"abstract":"Stimulator of interferon genes (STING) agonists have shown promise in cancer immunotherapy by enhancing type I interferon (IFN-I) signaling. However, the antiviral effects of IFN-I can suppress viral replication, limiting their combination with oncolytic viruses. This study demonstrates that combining a naturally isolated Senecavirus A (SVA) strain with the STING agonist MSA-2 supports synergistic IFN-I activation across multiple tumor models. The combination induces robust innate and adaptive antitumor immune responses without impairing SVA replication. Transcriptomics, immunoblotting and early IRF7 nuclear translocation in B16‑F10 cells are consistent with engagement of the RIG‑I/MDA5–TBK1–IRF7 axis. In vivo, co‑treatment enhanced IFN‑β induction, increased CD8⁺ T‑cell infiltration and reduced tumor burden relative to monotherapies, whereas efficacy was not observed in athymic nude mice, supporting T‑cell dependence. Together, these data provide preclinical evidence that a rational oncolytic virus and STING combination can amplify antitumor immunity without overtly compromising viral persistence.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 9","pages":"809-822"},"PeriodicalIF":7.3,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-06DOI: 10.1038/s41388-026-03686-z
Ting-Ting Yin, Meng-Xing Huang, Meng-Chu Liu, Pan-Yue Luo, Tian-tian Da, Chuan Huang, Ping Yang, Yuan Yao, Jie Cao
Immunotherapy remains ineffective for a wide variety of solid tumors due to the existence of tumor immune evasion. Although the transcription factor ETV5 is recognized for its oncogenic roles in tumor progression, its role in remodeling the immunosuppressive microenvironment remains largely unexplored. Here, we reveal that tumor-intrinsic ETV5 drives immune evasion and immune checkpoint inhibitor (ICI) resistance by enhancing the expansion and recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Genetic silencing of ETV5 in murine tumor models suppressed PMN-MDSCs differentiation from myeloid progenitors, reduced their tumor infiltration, and attenuated immunosuppressive function, resulting in enhanced cytotoxic T cell activity and delayed tumor progression. Mechanistically, ETV5 directly binds to the JH1 domain of JAK2, inducing its dimerization and phosphorylation, which activates STAT3 to transcriptionally upregulate CCL2 and recruit PMN-MDSCs. Therapeutically, ETV5 ablation synergized with anti-PD-L1 therapy to enhance tumor control, mirroring clinical observations where high ETV5 expression predicted immunotherapy resistance. Our study uncovers a non-canonical, transcription-independent role of ETV5 in orchestrating the JAK2/STAT3/CCL2 axis to sustain PMN-MDSC-mediated immune evasion, proposing ETV5 as a druggable target to overcome ICI resistance in solid tumors.
{"title":"Tumor-intrinsic ETV5 expression promotes PMN-MDSC-mediated immune evasion and immune checkpoint inhibitor resistance by activating the JAK2/STAT3/CCL2 axis","authors":"Ting-Ting Yin, Meng-Xing Huang, Meng-Chu Liu, Pan-Yue Luo, Tian-tian Da, Chuan Huang, Ping Yang, Yuan Yao, Jie Cao","doi":"10.1038/s41388-026-03686-z","DOIUrl":"10.1038/s41388-026-03686-z","url":null,"abstract":"Immunotherapy remains ineffective for a wide variety of solid tumors due to the existence of tumor immune evasion. Although the transcription factor ETV5 is recognized for its oncogenic roles in tumor progression, its role in remodeling the immunosuppressive microenvironment remains largely unexplored. Here, we reveal that tumor-intrinsic ETV5 drives immune evasion and immune checkpoint inhibitor (ICI) resistance by enhancing the expansion and recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Genetic silencing of ETV5 in murine tumor models suppressed PMN-MDSCs differentiation from myeloid progenitors, reduced their tumor infiltration, and attenuated immunosuppressive function, resulting in enhanced cytotoxic T cell activity and delayed tumor progression. Mechanistically, ETV5 directly binds to the JH1 domain of JAK2, inducing its dimerization and phosphorylation, which activates STAT3 to transcriptionally upregulate CCL2 and recruit PMN-MDSCs. Therapeutically, ETV5 ablation synergized with anti-PD-L1 therapy to enhance tumor control, mirroring clinical observations where high ETV5 expression predicted immunotherapy resistance. Our study uncovers a non-canonical, transcription-independent role of ETV5 in orchestrating the JAK2/STAT3/CCL2 axis to sustain PMN-MDSC-mediated immune evasion, proposing ETV5 as a druggable target to overcome ICI resistance in solid tumors.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 8","pages":"774-789"},"PeriodicalIF":7.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-06DOI: 10.1038/s41388-026-03682-3
G. N. Brooke, D. A. Leach, R. L. Culley, A. Azadova, L. Latonen, E. Rees, M. A. Alkheilewi, A. C. Pine, F. M. Fioretti, C. S. Reader, S. M. Powell, V. Reebye, J. Waxman, T. Visakorpi, C. L. Bevan
Prostate cancer is dependent upon the androgen receptor (AR), the activity of which is modified by cofactors that either enhance or repress its activity, often in a context-dependent manner. FUS/TLS is a multifunctional protein known to be important in multiple cancer types; in prostate cancer, we previously showed that FUS has a potential tumour suppressor role. Here, transcriptomic analysis of the LNCaP prostate cancer cell line shows a significant overlap in genes regulated by FUS and the androgen receptor. We demonstrate that FUS can regulate androgen receptor activity, in either direction, but predominantly represses androgen signalling. Reporter assays and domain-specific analyses of FUS identified mechanisms by which FUS modifies androgen receptor activity. FUS interacts with the androgen receptor and other cofactors to repress transcription; ChIP assays suggest that repression occurs via disassembly of the transcriptional complex. Quantitative proteomics and RNA-Seq were used to investigate FUS expression in patient samples across prostate cancer stages. FUS was found to be down-regulated in primary tumours, but up-regulated in advanced aggressive stages. These findings suggest that in early prostate cancer, FUS represses AR activity and tumour progression, leading to its down-regulation. In contrast, increased FUS expression in advanced disease appears to be linked to a loss of AR regulatory control.
{"title":"Disruption of androgen receptor-cofactor interactions by the RNA-binding protein FUS/TLS alters androgen signalling in prostate cancer","authors":"G. N. Brooke, D. A. Leach, R. L. Culley, A. Azadova, L. Latonen, E. Rees, M. A. Alkheilewi, A. C. Pine, F. M. Fioretti, C. S. Reader, S. M. Powell, V. Reebye, J. Waxman, T. Visakorpi, C. L. Bevan","doi":"10.1038/s41388-026-03682-3","DOIUrl":"10.1038/s41388-026-03682-3","url":null,"abstract":"Prostate cancer is dependent upon the androgen receptor (AR), the activity of which is modified by cofactors that either enhance or repress its activity, often in a context-dependent manner. FUS/TLS is a multifunctional protein known to be important in multiple cancer types; in prostate cancer, we previously showed that FUS has a potential tumour suppressor role. Here, transcriptomic analysis of the LNCaP prostate cancer cell line shows a significant overlap in genes regulated by FUS and the androgen receptor. We demonstrate that FUS can regulate androgen receptor activity, in either direction, but predominantly represses androgen signalling. Reporter assays and domain-specific analyses of FUS identified mechanisms by which FUS modifies androgen receptor activity. FUS interacts with the androgen receptor and other cofactors to repress transcription; ChIP assays suggest that repression occurs via disassembly of the transcriptional complex. Quantitative proteomics and RNA-Seq were used to investigate FUS expression in patient samples across prostate cancer stages. FUS was found to be down-regulated in primary tumours, but up-regulated in advanced aggressive stages. These findings suggest that in early prostate cancer, FUS represses AR activity and tumour progression, leading to its down-regulation. In contrast, increased FUS expression in advanced disease appears to be linked to a loss of AR regulatory control.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 8","pages":"757-773"},"PeriodicalIF":7.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03682-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-06DOI: 10.1038/s41388-026-03689-w
Suryavathi Viswanadhapalli, Tae-Kyung Lee, Scott Elmore, Gaurav Sharma, Rahul Gopalam, Durga Meenakshi Panneerdoss, Xihui Liu, Karla Parra, Tanner Reese, Michael Hsieh, Uday P. Pratap, Xue Yang, Behnam Ebrahimi, Xiaonan Li, Henry Neal, Chia-Yuan Chen, Kara Kassees, Christian Cervantes, Adriana Baker, Panneerdoss Subbarayalu, Paulina Ramirez, Yasmin A. Lyons, Zhao Lai, Yidong Chen, Joseph W. Boerma, Peter M. LoCoco, Nicholas A. Clanton, Zhenming Xu, Manjeet Rao, Tekmal Rajeshwar Rao, Edward Kost, Gangadhara R. Sareddy, Ganesh V. Raj, Jung-Mo Ahn, Ratna K. Vadlamudi
Ovarian cancer (OCa) remains the most lethal gynecologic malignancy in the United States, with a five-year survival rate below 20%. Elevated basal levels of endoplasmic reticulum stress (ERS) have recently emerged as a therapeutic vulnerability in OCa. We have previously shown that the tris-benzamide ERX-41 can induce ERS and cancer cell death in OCa by targeting LIPA. In this study, using iterative structure–activity relationship–guided studies to enhance activity in OCa, we identified a more potent ERX-41-derived analog, ERX-208. Importantly, ERX-208 consistently and significantly reduced cell viability in 23 OCa cell lines spanning five major histological OCa subtypes, with IC₅₀ values ranging from 50–100 nM, compared to ∼500 nM for ERX-41. Notably, ERX-208 showed minimal cytotoxicity toward normal ovarian surface epithelial cells, indicating cancer cell selectivity. ERX-208 induced apoptosis and suppressed colony formation in vitro in OCa cells. Mechanistic studies using RNA sequencing, Western blotting, RT-qPCR, transmission electron microscopy, and immunohistochemistry validated robust activation of ERS pathways upon ERX-208 treatment. Through in silico molecular docking simulation and confirmatory detailed site-directed mutagenesis, we identified that ERX-208 binds to LIPA over a broader interaction surface than ERX-41. At the 10 mg/kg dose, ERX-208 demonstrated favorable biodistribution, no observable toxicity, and potent antitumor efficacy in vivo against established cell line-derived xenograft (CDX), patient-derived xenograft (PDX), and patient-derived explant (PDE) models. Immunohistochemical analysis of treated tumors demonstrated changes in expression of proliferative marker (ki67, decreased) and the ERS marker (GRP78, increased). These findings support the clinical advancement of ERX-208 for the treatment of patients with OCa.
{"title":"Therapeutic optimization of LIPA targeting to induce endoplasmic reticulum stress and cell death in ovarian cancer","authors":"Suryavathi Viswanadhapalli, Tae-Kyung Lee, Scott Elmore, Gaurav Sharma, Rahul Gopalam, Durga Meenakshi Panneerdoss, Xihui Liu, Karla Parra, Tanner Reese, Michael Hsieh, Uday P. Pratap, Xue Yang, Behnam Ebrahimi, Xiaonan Li, Henry Neal, Chia-Yuan Chen, Kara Kassees, Christian Cervantes, Adriana Baker, Panneerdoss Subbarayalu, Paulina Ramirez, Yasmin A. Lyons, Zhao Lai, Yidong Chen, Joseph W. Boerma, Peter M. LoCoco, Nicholas A. Clanton, Zhenming Xu, Manjeet Rao, Tekmal Rajeshwar Rao, Edward Kost, Gangadhara R. Sareddy, Ganesh V. Raj, Jung-Mo Ahn, Ratna K. Vadlamudi","doi":"10.1038/s41388-026-03689-w","DOIUrl":"10.1038/s41388-026-03689-w","url":null,"abstract":"Ovarian cancer (OCa) remains the most lethal gynecologic malignancy in the United States, with a five-year survival rate below 20%. Elevated basal levels of endoplasmic reticulum stress (ERS) have recently emerged as a therapeutic vulnerability in OCa. We have previously shown that the tris-benzamide ERX-41 can induce ERS and cancer cell death in OCa by targeting LIPA. In this study, using iterative structure–activity relationship–guided studies to enhance activity in OCa, we identified a more potent ERX-41-derived analog, ERX-208. Importantly, ERX-208 consistently and significantly reduced cell viability in 23 OCa cell lines spanning five major histological OCa subtypes, with IC₅₀ values ranging from 50–100 nM, compared to ∼500 nM for ERX-41. Notably, ERX-208 showed minimal cytotoxicity toward normal ovarian surface epithelial cells, indicating cancer cell selectivity. ERX-208 induced apoptosis and suppressed colony formation in vitro in OCa cells. Mechanistic studies using RNA sequencing, Western blotting, RT-qPCR, transmission electron microscopy, and immunohistochemistry validated robust activation of ERS pathways upon ERX-208 treatment. Through in silico molecular docking simulation and confirmatory detailed site-directed mutagenesis, we identified that ERX-208 binds to LIPA over a broader interaction surface than ERX-41. At the 10 mg/kg dose, ERX-208 demonstrated favorable biodistribution, no observable toxicity, and potent antitumor efficacy in vivo against established cell line-derived xenograft (CDX), patient-derived xenograft (PDX), and patient-derived explant (PDE) models. Immunohistochemical analysis of treated tumors demonstrated changes in expression of proliferative marker (ki67, decreased) and the ERS marker (GRP78, increased). These findings support the clinical advancement of ERX-208 for the treatment of patients with OCa.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 8","pages":"790-804"},"PeriodicalIF":7.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03689-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132760","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}
Bladder cancer remains a clinically challenging malignancy, with increasing evidence suggesting that chronic bladder inflammation, such as interstitial cystitis (IC), may contribute to its development. However, the molecular mechanisms linking inflammation to tumorigenesis are poorly understood. Here, we identify coiled-coil domain-containing 8 (CCDC8) as a potential oncogenic factor in bladder cancer. Transcriptomic analysis revealed that CCDC8 is dysregulated in both IC and bladder cancer, with overexpression confirmed in tumor tissues and cell lines. Elevated CCDC8 expression was significantly associated with advanced tumor stage, lymph node metastasis, and poor prognosis, particularly in patients harboring wild-type TP53. Functional studies demonstrated that CCDC8 promotes tumor cell proliferation, migration, and survival in vitro, and enhances tumor growth in vivo. Mechanistically, CCDC8 interacts with the E3 ubiquitin ligase scaffold protein CUL7, facilitating proteasome-dependent degradation of P53, thereby suppressing its downstream effectors such as P21 and BAX. Pharmacological inhibition of neddylation with MLN4924 restored P53 levels and reversed the oncogenic effects of CCDC8 both in vitro and in vivo. Together, these findings highlight a novel mechanism of P53 regulation in bladder cancer, position CCDC8 as a potential biomarker and therapeutic target, and suggest a molecular link between chronic bladder inflammation and malignant transformation.
{"title":"Interstitial cystitis-related gene CCDC8 accelerates tumorigenesis by participating in CUL7-mediated degradation of P53 in bladder cancer","authors":"Jiawen Wang, Jinfu Wang, Lingfeng Meng, Xinhao Wang, Zehao Yan, Honghong Pan, Jiayue Wu, Qidong Zhou, Liefu Ye, Jinfeng Wu, Yaoguang Zhang, Jianye Wang","doi":"10.1038/s41388-026-03688-x","DOIUrl":"10.1038/s41388-026-03688-x","url":null,"abstract":"Bladder cancer remains a clinically challenging malignancy, with increasing evidence suggesting that chronic bladder inflammation, such as interstitial cystitis (IC), may contribute to its development. However, the molecular mechanisms linking inflammation to tumorigenesis are poorly understood. Here, we identify coiled-coil domain-containing 8 (CCDC8) as a potential oncogenic factor in bladder cancer. Transcriptomic analysis revealed that CCDC8 is dysregulated in both IC and bladder cancer, with overexpression confirmed in tumor tissues and cell lines. Elevated CCDC8 expression was significantly associated with advanced tumor stage, lymph node metastasis, and poor prognosis, particularly in patients harboring wild-type TP53. Functional studies demonstrated that CCDC8 promotes tumor cell proliferation, migration, and survival in vitro, and enhances tumor growth in vivo. Mechanistically, CCDC8 interacts with the E3 ubiquitin ligase scaffold protein CUL7, facilitating proteasome-dependent degradation of P53, thereby suppressing its downstream effectors such as P21 and BAX. Pharmacological inhibition of neddylation with MLN4924 restored P53 levels and reversed the oncogenic effects of CCDC8 both in vitro and in vivo. Together, these findings highlight a novel mechanism of P53 regulation in bladder cancer, position CCDC8 as a potential biomarker and therapeutic target, and suggest a molecular link between chronic bladder inflammation and malignant transformation.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 8","pages":"745-756"},"PeriodicalIF":7.3,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146126018","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}
Emerging research highlights the key role of the central nervous system in regulating peripheral tumor progression via neural, neuroendocrine, and immune pathways. Although direct evidence linking the brain to peripheral tumor initiation remains limited, recent studies using retrograde tracing have revealed anatomical and functional circuits between specific brain regions and peripheral solid tumors. These circuits influence malignant, stromal, and immune cells within the tumor microenvironment, as well as systemic immune and metabolic processes. In this review, we synthesize current findings on brain-periphery neural networks across multiple cancer types and discuss how tumor burden can reshape brain activity, contributing to emotional and cognitive disturbances, and how the brain, in turn, regulates tumor biology. In particular, we address the translational potential of targeting brain-tumor circuits via neuromodulation, behavioral interventions, and lifestyle-based therapies. Understanding these bidirectional communications offers new approaches for systemic, integrative therapeutic strategies.
{"title":"Brain-cancer interactions outside the CNS","authors":"Weihan Li, Ruixue Huo, Sailiang Liu, Kexin He, Hao Wu, Hao Wang, Shu-Heng Jiang, Junli Xue","doi":"10.1038/s41388-026-03684-1","DOIUrl":"10.1038/s41388-026-03684-1","url":null,"abstract":"Emerging research highlights the key role of the central nervous system in regulating peripheral tumor progression via neural, neuroendocrine, and immune pathways. Although direct evidence linking the brain to peripheral tumor initiation remains limited, recent studies using retrograde tracing have revealed anatomical and functional circuits between specific brain regions and peripheral solid tumors. These circuits influence malignant, stromal, and immune cells within the tumor microenvironment, as well as systemic immune and metabolic processes. In this review, we synthesize current findings on brain-periphery neural networks across multiple cancer types and discuss how tumor burden can reshape brain activity, contributing to emotional and cognitive disturbances, and how the brain, in turn, regulates tumor biology. In particular, we address the translational potential of targeting brain-tumor circuits via neuromodulation, behavioral interventions, and lifestyle-based therapies. Understanding these bidirectional communications offers new approaches for systemic, integrative therapeutic strategies.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 7","pages":"715-727"},"PeriodicalIF":7.3,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146113787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-02DOI: 10.1038/s41388-026-03687-y
Yi-Zhe Ren, Ming-Na Zhao, Feng-Lin Du, Lei Wu, Lin Wang, Jia-Tao Lou
Bone metastasis is a devastating complication of non-small cell lung cancer (NSCLC), critically impairing patient survival. Nevertheless, the underlying molecular mechanisms driving this aggressive process remain incompletely elucidated. To systematically investigate these mechanisms, we compared a highly bone-metastatic NSCLC subpopulation with its parental cells. Notably, we identified elevated expression of O-linked β-N-acetylglucosamine transferase (OGT) in the metastatic subpopulation. We further demonstrated that O-GlcNAcylation at the Ser199 site of the nuclear pore protein POM121 is markedly increased and drives NSCLC bone metastasis. Mechanistically, O-GlcNAcylation of POM121 attenuates its interaction with the E3 ubiquitin ligase TRIM21, thus antagonizing ubiquitination and stabilizing POM121. Accumulated POM121 enhances the nuclear import of the oncogenic transcription factor c-MYC. Nuclear c-MYC subsequently orchestrates transcriptional activation of downstream extracellular matrix (ECM)-related genes. Collectively, we elucidate a previously unrecognized OGT-POM121-c-MYC-ECM axis that critically drives NSCLC bone metastasis. Crucially, clinical analysis reveals that high levels of OGT, POM121, and c-MYC positively correlate with adverse clinical outcomes. These findings establish the OGT-POM121-c-MYC-ECM axis as a potential diagnostic biomarker and a promising therapeutic target for NSCLC bone metastasis.
骨转移是非小细胞肺癌（NSCLC）的一种破坏性并发症，严重损害患者的生存。然而，驱动这一侵略性过程的潜在分子机制仍未完全阐明。为了系统地研究这些机制，我们比较了一个高度骨转移的非小细胞肺癌亚群与其亲本细胞。值得注意的是，我们发现O-linked β- n -乙酰氨基葡萄糖转移酶（OGT）在转移亚群中的表达升高。我们进一步证明，核孔蛋白POM121 Ser199位点的o - glcn酰化显著增加，并驱动NSCLC骨转移。机制上，POM121的o - glcn酰化减弱了其与E3泛素连接酶TRIM21的相互作用，从而拮抗泛素化并稳定POM121。累积的POM121增强了致癌转录因子c-MYC的核输入。核c-MYC随后协调下游细胞外基质（ECM）相关基因的转录激活。总之，我们阐明了先前未被识别的OGT-POM121-c-MYC-ECM轴，该轴对NSCLC骨转移至关重要。至关重要的是，临床分析显示，高水平的OGT、POM121和c-MYC与不良临床结果呈正相关。这些发现确立了OGT-POM121-c-MYC-ECM轴作为一种潜在的诊断生物标志物和非小细胞肺癌骨转移的治疗靶点。
{"title":"POM121 O-GlcNAcylation facilitates bone metastasis in non-small cell lung cancer through enhanced c-MYC nuclear import and ECM reprogramming","authors":"Yi-Zhe Ren, Ming-Na Zhao, Feng-Lin Du, Lei Wu, Lin Wang, Jia-Tao Lou","doi":"10.1038/s41388-026-03687-y","DOIUrl":"10.1038/s41388-026-03687-y","url":null,"abstract":"Bone metastasis is a devastating complication of non-small cell lung cancer (NSCLC), critically impairing patient survival. Nevertheless, the underlying molecular mechanisms driving this aggressive process remain incompletely elucidated. To systematically investigate these mechanisms, we compared a highly bone-metastatic NSCLC subpopulation with its parental cells. Notably, we identified elevated expression of O-linked β-N-acetylglucosamine transferase (OGT) in the metastatic subpopulation. We further demonstrated that O-GlcNAcylation at the Ser199 site of the nuclear pore protein POM121 is markedly increased and drives NSCLC bone metastasis. Mechanistically, O-GlcNAcylation of POM121 attenuates its interaction with the E3 ubiquitin ligase TRIM21, thus antagonizing ubiquitination and stabilizing POM121. Accumulated POM121 enhances the nuclear import of the oncogenic transcription factor c-MYC. Nuclear c-MYC subsequently orchestrates transcriptional activation of downstream extracellular matrix (ECM)-related genes. Collectively, we elucidate a previously unrecognized OGT-POM121-c-MYC-ECM axis that critically drives NSCLC bone metastasis. Crucially, clinical analysis reveals that high levels of OGT, POM121, and c-MYC positively correlate with adverse clinical outcomes. These findings establish the OGT-POM121-c-MYC-ECM axis as a potential diagnostic biomarker and a promising therapeutic target for NSCLC bone metastasis.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"45 7","pages":"728-743"},"PeriodicalIF":7.3,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41388-026-03687-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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