Cancer gene therapy最新文献

Dual PI3K/AKT/mTOR and CDK4/6 inhibition suppresses survivin to overcome uterine dedifferentiated endometrial carcinoma. 双抑制PI3K/AKT/mTOR和CDK4/6抑制survivin克服子宫去分化子宫内膜癌。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-05-08 DOI: 10.1038/s41417-026-01039-2

Yun-Hsin Tang, Cheng-Lung Hsu, Angel Chao, Chyong-Huey Lai, Shih-Ming Jung, Yun-Shien Lee, Ying-Chih Chang, Chiao-Yun Lin

{"title":"Dual PI3K/AKT/mTOR and CDK4/6 inhibition suppresses survivin to overcome uterine dedifferentiated endometrial carcinoma.","authors":"Yun-Hsin Tang, Cheng-Lung Hsu, Angel Chao, Chyong-Huey Lai, Shih-Ming Jung, Yun-Shien Lee, Ying-Chih Chang, Chiao-Yun Lin","doi":"10.1038/s41417-026-01039-2","DOIUrl":"https://doi.org/10.1038/s41417-026-01039-2","url":null,"abstract":"Undifferentiated/dedifferentiated endometrial carcinoma (UEC/DEC, collectively referred to as UDEC) is a rare but highly aggressive subtype of endometrial cancer, characterized by strong metastatic potential, frequent recurrence, and resistance to conventional chemotherapy. Currently, there is no standardized treatment strategy for UDEC. Genomic profiling has revealed a high frequency of PTEN mutations, resulting in dysregulation of the PI3K/AKT/mTOR and cell cycle pathways. To investigate therapeutic options, we utilized patient-derived xenograft (PDX) and tumoroid models established from PDX tumors derived from UDEC patient samples to evaluate everolimus (an mTOR inhibitor) and palbociclib (a CDK4/6 inhibitor), alone and in combination. Combination therapy exhibited antitumor effects in UDEC cell lines and tumoroids and significantly suppressed tumor growth in PDX models without inducing weight loss in mice. RNA sequencing of treated PDX tumors identified survivin as a consistently downregulated target. Mechanistically, the combination reduced Sp1-mediated transcription of survivin. In a clinical cohort of 29 UDEC patients, higher survivin expression showed a trend toward shorter overall and progression-free survival, supporting its role as a prognostic biomarker. These findings highlight dual PI3K/AKT/mTOR and CDK4/6 inhibition as a promising strategy for UDEC and demonstrate the translational value of PDX and tumoroid models in aggressive gynecologic cancers.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MSTO1 modulates RAD51 activity to safeguard mitochondrial DNA integrity and control immune responses. MSTO1调节RAD51活性，以保护线粒体DNA的完整性和控制免疫反应。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-05-07 DOI: 10.1038/s41417-026-01032-9

Kaiqi Cheng, Zhanzhan Xu, Jiansong Liu, Yichen Pan, Chen Nie, Zuchao Mao, Haodong Lin, Yingyu Qin, Shuqi Cao, Xiaoman Li, Weibin Wang, Shiwei Li, Jiadong Wang

{"title":"MSTO1 modulates RAD51 activity to safeguard mitochondrial DNA integrity and control immune responses.","authors":"Kaiqi Cheng, Zhanzhan Xu, Jiansong Liu, Yichen Pan, Chen Nie, Zuchao Mao, Haodong Lin, Yingyu Qin, Shuqi Cao, Xiaoman Li, Weibin Wang, Shiwei Li, Jiadong Wang","doi":"10.1038/s41417-026-01032-9","DOIUrl":"https://doi.org/10.1038/s41417-026-01032-9","url":null,"abstract":"Pathogenic MSTO1 mutations cause cerebellar ataxia and congenital myopathy, yet their molecular mechanisms remain poorly understood. This study identifies MSTO1 as a crucial regulator of mitochondrial genome integrity through direct interaction with RAD51. MSTO1 deficiency enhances RAD51 binding to mitochondrial DNA (mtDNA), disrupting mtDNA replication and causing mtDNA damage. This interaction, mediated by the conserved FxxA motif, specifically regulates RAD51's mitochondrial activity without affecting its nuclear roles. Loss of MSTO1 impairs mitochondrial membrane potential, reduces mtDNA content, and increases susceptibility to oxidative stress. Furthermore, MSTO1 deficiency triggers BAX/BAK-dependent mtDNA leakage, activating the cGAS-STING pathway and driving inflammatory responses. Clinical bioinformatics further link low MSTO1 expression with immune activation in cancers. Our findings establish MSTO1 as a modulator of RAD51 activity within mitochondria, regulating mitochondrial stability and immune responses. This provides insights into MSTO1-related diseases and suggests MSTO1 as a potential target for activating anti-tumor immune responses in cancer cells.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

b-AP15 enhances TRAIL-induced cell death in HNSCC via the induction of ROS/JNK/DR5 signalling. b-AP15通过诱导ROS/JNK/DR5信号传导增强trail诱导的HNSCC细胞死亡。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-05-02 DOI: 10.1038/s41417-026-01038-3

Fin T A Brown, Lucy Quesne, Louisa M Wootton, Holly Foxell, Ipek Erseven, Emilia Ewen Benns, Molly Tate, Ethan L Morgan

{"title":"b-AP15 enhances TRAIL-induced cell death in HNSCC via the induction of ROS/JNK/DR5 signalling.","authors":"Fin T A Brown, Lucy Quesne, Louisa M Wootton, Holly Foxell, Ipek Erseven, Emilia Ewen Benns, Molly Tate, Ethan L Morgan","doi":"10.1038/s41417-026-01038-3","DOIUrl":"https://doi.org/10.1038/s41417-026-01038-3","url":null,"abstract":"Therapeutic resistance to chemotherapy or radiotherapy is a significant issue in several cancers, including head and neck squamous cell carcinoma (HNSCC). One pathway associated with therapeutic resistance is the NFκB pathway, which promotes survival in response to the cytokine TNFα, a key mediator of chemotherapy and radiotherapy-induced cytotoxicity. However, direct targeting of the NFκB pathway is associated with significant toxicity and thus targeting the regulation of this pathway is a promising therapeutic target. We recently demonstrated that the USP14/UCHL5 inhibitor b-AP15 inhibits NFκB activity, inhibiting proliferation and inducing apoptosis in HNSCC cells. Furthermore, b-AP15 treatment sensitised HNSCC cells to the cytotoxic effects of TNFα, as well as TNF-inducing radiation treatment. Here, we investigated if b-AP15 sensitised HNSCC cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a cancer selective member of the TNF family. b-AP15 treatment sensitised HNSCC cells to TRAIL treatment. Mechanistically, we show that b-AP15 induced expression of the TRAIL receptor Death Receptor 5 (DR5)/TRAIL Receptor 2 (TRAILR2), which was required for b-AP15-mediated TRAIL sensitisation. b-AP15 induced reactive oxygen species (ROS) and activated the JNK signalling pathway and both ROS and JNK signalling were required for the induction of DR5 expression and TRAIL sensitisation. We further show that b-AP15-mediated reduction of the NFκB-dependent gene XIAP induced DR5 expression and TRAIL sensitisation and that combination between b-AP15 and IAP antagonists was synergistic in HNSCC cells in vitro. Our data further define the mechanism of b-AP15-mediated cytotoxicity and highlight potential combination treatments that warrant further exploration in pre-clinical studies in HNSCC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

YTHDF1/SLC39A4 signaling axis promotes gastric cancer cell proliferation by suppressing cuproptosis ex vivo and in vitro. YTHDF1/SLC39A4信号轴通过抑制体内外cuprotic促进胃癌细胞增殖。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-04-29 DOI: 10.1038/s41417-026-01036-5

Jingying Su, Jihan Qi, Binhua Xu, Jiaxin Wang, Ram Prasad Chaulagain, Hongliang Chen, Ning Li, Xinyu Jiang, Lingyi Xu, Fengchun Li, Wenli Mao, Shizhu Jin

{"title":"YTHDF1/SLC39A4 signaling axis promotes gastric cancer cell proliferation by suppressing cuproptosis ex vivo and in vitro.","authors":"Jingying Su, Jihan Qi, Binhua Xu, Jiaxin Wang, Ram Prasad Chaulagain, Hongliang Chen, Ning Li, Xinyu Jiang, Lingyi Xu, Fengchun Li, Wenli Mao, Shizhu Jin","doi":"10.1038/s41417-026-01036-5","DOIUrl":"https://doi.org/10.1038/s41417-026-01036-5","url":null,"abstract":"Gastric cancer (GC) continues to be a major contributor to global cancer mortality, underscoring the need to elucidate its molecular mechanisms to develop effective therapies. Cuproptosis, a copper-dependent form of cell death, exhibits tumor-suppressive effects in GC. Clinical specimens revealed elevated expression of solute carrier family 39 member 4 (SLC39A4) in GC tissues, correlating with poor prognosis. However, the role of SLC39A4 in GC remains unclear. Using lentiviral transduction in AGS and MKN-45 cell lines, we established stable monoclonal strains with SLC39A4 overexpression and knockdown for functional studies. SLC39A4 promotes GC cell proliferation both in vitro and in vivo. CuCl2 and elesclomol treatment induced cuproptosis, which was attenuated by SLC39A4 overexpression but potentiated by SLC39A4 knockdown, as confirmed through proliferation assays and cuproptosis marker analyses in cell cultures and xenograft models. Mechanistically, the m6A reader protein YTHDF1, frequently overexpressed in GC patients and known to inhibit elesclomol-induced cuproptosis, bound to SLC39A4 mRNA and stabilized its transcripts. Dual-luciferase assays demonstrated that mutation of the m6A site within SLC39A4's coding sequence abolished YTHDF1-mediated regulation. These findings establish SLC39A4 as a promoter of GC progression through cuproptosis suppression, modulated by YTHDF1 via m6A-dependent mRNA stabilization, revealing potential therapeutic targets for GC treatment.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Preclinical development of a mutant KRAS targeting therapeutic cancer vaccine. 靶向治疗性癌症疫苗KRAS突变体的临床前研究

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-04-28 DOI: 10.1038/s41417-026-01034-7

Catarina Pinto, Romana Bischl, Lea Knezevic, Sarah Ahmadi-Erber, Katell Bidet Huang, Sarah Schmidt, Peter Steinberger, Klaus K Orlinger, Henning Lauterbach, Josipa Raguz

{"title":"Preclinical development of a mutant KRAS targeting therapeutic cancer vaccine.","authors":"Catarina Pinto, Romana Bischl, Lea Knezevic, Sarah Ahmadi-Erber, Katell Bidet Huang, Sarah Schmidt, Peter Steinberger, Klaus K Orlinger, Henning Lauterbach, Josipa Raguz","doi":"10.1038/s41417-026-01034-7","DOIUrl":"https://doi.org/10.1038/s41417-026-01034-7","url":null,"abstract":"KRAS mutations are frequent oncogenic drivers in several indications, yet limited targeted therapy options are available. Here we engineered our clinically validated artARENA platform to develop an \"off-the-shelf\" shared neoantigen vaccine, capable of triggering potent CD8+ T-cell responses against the five most prevalent KRAS mutations (G12D, G12V, G12C, G12R, and G13D). Alternating two-vector therapy (sequential administration of artPICV-based vector followed by artLCMV-based vector, encoding the same optimized antigen construct) induced KRAS neoepitope-specific polyfunctional T-cell responses in HLA transgenic mouse strains, showing direct cytotoxicity against KRAS-mutant cell targets in an in vivo assay. Importantly, no cross-reactivity to wt KRAS was observed, highlighting the safety of the approach. Immunogenicity data in mice was corroborated in vitro using T cell stimulation assays, confirming the antigenicity of the construct. Taken together, these results and the clinically validated favorable safety and immunogenicity profiles of our platform warrant clinical translation of this program with the aim to provide more durable and comprehensive tumor control in patients harboring KRAS mutated tumors.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Application of CAR-T therapy in solid tumors: current opportunities and challenges. CAR-T疗法在实体肿瘤中的应用：当前的机遇与挑战。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-04-27 DOI: 10.1038/s41417-026-01033-8

Aixin Wang, Xinyu Ye, Yumeng Zhao, Dayong Huang, Chao Zhang

{"title":"Application of CAR-T therapy in solid tumors: current opportunities and challenges.","authors":"Aixin Wang, Xinyu Ye, Yumeng Zhao, Dayong Huang, Chao Zhang","doi":"10.1038/s41417-026-01033-8","DOIUrl":"https://doi.org/10.1038/s41417-026-01033-8","url":null,"abstract":"In recent years, chimeric antigen receptor T-cell (CAR-T) therapy has achieved substantial progress in treating hematologic malignancies. However, its efficacy in solid tumors remains limited due to various biological and logistical challenges. This review systematically summarizes the advancements in CAR-T therapy for solid tumors, including lung cancer, pancreatic cancer, neuroblastoma, and breast cancer. It traces the progression of CAR-T cell design from the first to the fifth generation and explores the roles of key functional modules, such as scFv, hinge regions, and costimulatory domains. Major barriers to CAR-T application in solid tumors are discussed, including antigen heterogeneity, the lack of specific targets, CAR-T cell exhaustion, the immunosuppressive tumor microenvironment (TME), and physical barriers within tumor tissues. Additionally, the review highlights emerging strategies and recent developments from 2023 to 2025, such as bispecific and multispecific CAR-T cells, regional administration techniques, logic-gated CAR constructs, safety switches, and novel approaches to modulating the TME. Despite considerable challenges, the integration of these cutting-edge technologies is advancing CAR-T therapy for solid tumors, providing new prospects for patients with refractory solid malignancies. Finally, future directions for CAR-T applications in solid tumors are discussed.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A p53 peptide mucosal vaccine induces cellular and humoral immunity and anti-tumor effects in a murine colorectal cancer model. p53肽粘膜疫苗在小鼠结直肠癌模型中诱导细胞和体液免疫及抗肿瘤作用。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-04-25 DOI: 10.1038/s41417-026-01035-6

Su He Wang, Zhengyi Cao, Katarzyna W Janczak, Ying Feng, Maranne Green, Shengzhuang Tang, Eric R Fearon, James R Baker

{"title":"A p53 peptide mucosal vaccine induces cellular and humoral immunity and anti-tumor effects in a murine colorectal cancer model.","authors":"Su He Wang, Zhengyi Cao, Katarzyna W Janczak, Ying Feng, Maranne Green, Shengzhuang Tang, Eric R Fearon, James R Baker","doi":"10.1038/s41417-026-01035-6","DOIUrl":"https://doi.org/10.1038/s41417-026-01035-6","url":null,"abstract":"Many patients with metastatic and recurrent colorectal cancer (CRC) have poor outcomes, due to resistance to current treatment approaches. Missense mutations in the TP53 gene are found in about 65% of CRCs, but no current treatment approach targets mutant TP53 activity. To develop a vaccine approach against CRCs expressing a mutant p53 protein, we used a murine CRC model with conditional expression of a Trp53 codon R270H missense allele, and immunized mice with the experimental vaccine, which combined a synthetic R270H p53 peptide and wild-type p53 recombinant protein with a mucosal nanoemulsion (NE) adjuvant. The p53/NE vaccine was administered intranasally to the mice after mutant p53 induction and tumor initiation. Vaccinated mice had markedly increased serum anti-p53 IgG, IgG2a, and IgG2b as compared to control mice. The vaccination also enhanced antigen-specific Th1 and Th17 cellular immune responses, as shown by increasing production of IFNγ, IL-17a and IL-2. The immunized animals had significantly decreased tumor size, prolonged survival and increased tumor CD8+ T cell infiltrates. Collectively, we have demonstrated a mucosal vaccine against mutated p53 protein in CRC can induce antigen-specific cellular and humoral immunity. The findings suggest potential value in pursuing mutated p53 as a vaccine target in CRC.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Amitriptyline inhibits EAG1 channels by binding to their PAS domains and exerts EAG1-dependent anti-tumorigenic effects. 阿米替林通过结合EAG1通道的PAS结构域抑制EAG1通道，并发挥EAG1依赖性的抗肿瘤作用。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-04-16 DOI: 10.1038/s41417-026-01029-4

Joos Berghausen, Clementine A D Thomas, Ze-Jun Wang, Kyle Kihn, Eric Glasgow, Tinatin I Brelidze

{"title":"Amitriptyline inhibits EAG1 channels by binding to their PAS domains and exerts EAG1-dependent anti-tumorigenic effects.","authors":"Joos Berghausen, Clementine A D Thomas, Ze-Jun Wang, Kyle Kihn, Eric Glasgow, Tinatin I Brelidze","doi":"10.1038/s41417-026-01029-4","DOIUrl":"https://doi.org/10.1038/s41417-026-01029-4","url":null,"abstract":"Ether-a-go-go 1 (EAG1) potassium channels are overexpressed in the majority of cancers, and inhibition of their activity decreases cancer growth and migration. Here, we show that amitriptyline (AmiT), an antidepressant that is also used for pain management in cancer patients, inhibits EAG1 by binding to their PAS domains and exerts EAG1-dependent anti-tumorigenic effects. AmiT inhibited the growth of MDA-MB-231 and SH-SY5Y cells expressing EAG1 at high levels, while having a smaller effect on the growth of A375 cells expressing EAG1 at lower levels. Knocking in EAG1 in HEK293 cells increased the inhibition of cell growth by AmiT, while knocking out EAG1 in MDA-MB-231 cells decreased the inhibition of cell growth by the drug. AmiT also inhibited cell migration in MDA-MB-231 and SH-SY5Y cells, while having no effect in A375 cells. Knocking out EAG1 in MDA-MB-231 cells completely removed the effect of AmiT on cell migration. Similar to the in vitro results, AmiT inhibited the growth of MDA-MB-231 and SH-SY5Y zebrafish xenografts, while having no effect on A375 xenografts. Taken together, these results indicate that EAG1 channels are a functional target of AmiT and suggest a potential repurposing of this FDA-approved drug as an anti-cancer agent for tumors with high EAG1 expression.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147697902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SPARC family proteins: matricellular modulators of cancer progression and therapeutic resistance. SPARC家族蛋白：癌症进展和治疗耐药性的基质细胞调节剂。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-04-14 DOI: 10.1038/s41417-026-01028-5

Rachel Huey Xuan Hoe, Thamil Selvee Ramasamy, Ajantha Sinniah, Ain Zubaidah Ayob

{"title":"SPARC family proteins: matricellular modulators of cancer progression and therapeutic resistance.","authors":"Rachel Huey Xuan Hoe, Thamil Selvee Ramasamy, Ajantha Sinniah, Ain Zubaidah Ayob","doi":"10.1038/s41417-026-01028-5","DOIUrl":"https://doi.org/10.1038/s41417-026-01028-5","url":null,"abstract":"The SPARC (secreted protein acidic and rich in cysteine) family represents a unique class of matricellular proteins - including SPARC, SPARCL1, SPOCK1-3, SMOC1-2, and FSTL1 - that regulate extracellular matrix (ECM) dynamics, cell signaling, and tissue homoeostasis. In cancer, their expression is frequently dysregulated, through epigenetic mechanisms, microRNAs, and interactions within the tumor microenvironment (TME). Dysregulation of SPARC family members is most pronounced in aggressive malignancies with SPARC, SPARCL1, SPOCK1, and SPOCK2 most consistently altered. These proteins drive tumor progression through ECM remodeling, epithelial-mesenchymal transition (EMT), maintenance of cancer stemness, immune modulation, and drug resistance acquisition. Their functions are highly context-dependent, exerting either tumor-suppressive or oncogenic effects depending on tissue types and disease stage. While their secreted nature positions family members as promising serum or plasma biomarkers, challenges such as ECM protein undruggability, functional heterogeneity, and the absence of upstream regulators have so far precluded direct therapeutic targeting, with no agents advancing to clinical trials. Nonetheless, indirect strategies leveraging their biology show preclinical promise. This review synthesizes current knowledge on SPARC family structure, regulation, and context-specific functions in cancer-TME interactions, emphasizing their dual roles as modulators of progression and resistance. By integrating mechanistic insights with translational advances, we highlight the emerging utility of SPARC family proteins in precision oncology and underscore the need for deeper understanding to enable effective biomarker development and targeted therapeutic strategies.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

WTAP stabilized by USP7 contributes to enzalutamide resistance in prostate cancer via mediating AKT m6A-modification USP7稳定的WTAP通过介导AKT m6a修饰参与前列腺癌对恩杂鲁胺的耐药。

IF 5 3区医学

Cancer gene therapy Pub Date : 2026-04-14 DOI: 10.1038/s41417-026-01013-y

Ruxue Shi, Kai Gu, Haichuan Li, Qingwei Sun, Xinyu Wu, Shuhong Huang, Qingxia Hu

{"title":"WTAP stabilized by USP7 contributes to enzalutamide resistance in prostate cancer via mediating AKT m6A-modification","authors":"Ruxue Shi, Kai Gu, Haichuan Li, Qingwei Sun, Xinyu Wu, Shuhong Huang, Qingxia Hu","doi":"10.1038/s41417-026-01013-y","DOIUrl":"10.1038/s41417-026-01013-y","url":null,"abstract":"Castration-resistant prostate cancer (CRPC) is one of the most prevalent cancers in men. The new generation androgen receptor (AR) inhibitor enzalutamide can improve the therapeutic effectiveness of patients with CRPC. However, these patients eventually develop acquired enzalutamide resistance (ENZR), and the mechanisms underlying resistance are not well understood. Wilms’ tumor 1-associating protein (WTAP) plays an important role in m6A modification and has been reported as an oncogene in various cancers. Here, we utilized a tissue microarray and collected tissues from prostate cancer (PCa) patients to detect WTAP expression, and found that WTAP is upregulated in PCa. Meanwhile, WTAP overexpression promotes cell proliferation and accelerates tumor growth through colony formation assays and the establishment of a subcutaneous xenograft model in vivo. These findings establish the tumor promoter role of WTAP in prostatic tumorigenesis. Furthermore, we verified that WTAP is a novel responsive gene of AR via promoter activity and chromatin immunoprecipitation (ChIP) assays. Importantly, we uncovered that WTAP is upregulated in ENZR cells, and WTAP knockdown inhibited the proliferation of ENZR cells. Mechanistically, ubiquitin-specific protease (USP7) enhanced the stability of WTAP by the ubiquitin-proteasome pathway in ENZR cells, thereby WTAP increases promote AKT signaling through an m6A-mediated way, and an AKT inhibitor can abolish the pro-resistance phenotype mediated by WTAP. Together, these findings suggest that WTAP plays a key role in ENZR development of PCa cells, and WTAP may be a potential treatment target for ENZR tumors.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"33 3","pages":"277-288"},"PeriodicalIF":5.0,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-026-01013-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147688419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0