Pub Date : 2025-09-10DOI: 10.1038/s43018-025-01051-9
Gabrielle Brewer
{"title":"Gut check for CAR T success","authors":"Gabrielle Brewer","doi":"10.1038/s43018-025-01051-9","DOIUrl":"10.1038/s43018-025-01051-9","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 9","pages":"1484-1484"},"PeriodicalIF":28.5,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033677","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 : 2025-09-04DOI: 10.1038/s43018-025-01030-0
We developed paclitaxome-2, an optimized version of the sphingomyelin-derived paclitaxel nanovesicle paclitaxome. Leveraging the cationization-enabled transcytosis machinery boosted tumor penetration, and incorporating CD47 ‘self’ peptide masking minimized phagocytosis. Co-delivery of gemcitabine or carboplatin improved therapeutic outcomes in advanced pancreatic cancer and post-surgical triple-negative breast cancer in mouse models.
{"title":"A sphingolipid-derived paclitaxel nanovesicle for improved cancer therapy","authors":"","doi":"10.1038/s43018-025-01030-0","DOIUrl":"10.1038/s43018-025-01030-0","url":null,"abstract":"We developed paclitaxome-2, an optimized version of the sphingomyelin-derived paclitaxel nanovesicle paclitaxome. Leveraging the cationization-enabled transcytosis machinery boosted tumor penetration, and incorporating CD47 ‘self’ peptide masking minimized phagocytosis. Co-delivery of gemcitabine or carboplatin improved therapeutic outcomes in advanced pancreatic cancer and post-surgical triple-negative breast cancer in mouse models.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 10","pages":"1619-1620"},"PeriodicalIF":28.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145001031","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 : 2025-09-02DOI: 10.1038/s43018-025-01034-w
Antti S. Rannikko
Prostate MRI has emerged as a way to improve accuracy in prostate cancer diagnostics. However, the subjectivity of assessments remains a challenge. New research shows that AI can help in this task and serve as a tool to improve MRI-based prediction of prostate cancer aggressiveness.
{"title":"Artificial intelligence for prostate cancer diagnostics","authors":"Antti S. Rannikko","doi":"10.1038/s43018-025-01034-w","DOIUrl":"10.1038/s43018-025-01034-w","url":null,"abstract":"Prostate MRI has emerged as a way to improve accuracy in prostate cancer diagnostics. However, the subjectivity of assessments remains a challenge. New research shows that AI can help in this task and serve as a tool to improve MRI-based prediction of prostate cancer aggressiveness.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 10","pages":"1613-1614"},"PeriodicalIF":28.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961899","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 : 2025-09-02DOI: 10.1038/s43018-025-01041-x
Lizhi Shao, Chao Liang, Ye Yan, Haibin Zhu, Xiaoming Jiang, Meiling Bao, Pan Zang, Xiazi Huang, Hongyu Zhou, Pei Nie, Liang Wang, Jie Li, Shudong Zhang, Shancheng Ren
Prostate cancer is a leading health concern for men, yet current clinical assessments of tumor aggressiveness rely on invasive procedures that often lead to inconsistencies. There remains a critical need for accurate, noninvasive diagnosis and grading methods. Here we developed a foundation model trained on multiparametric magnetic resonance imaging (MRI) and paired pathology data for noninvasive diagnosis and grading of prostate cancer. Our model, MRI-based Predicted Transformer for Prostate Cancer (MRI-PTPCa), was trained under contrastive learning on nearly 1.3 million image–pathology pairs from over 5,500 patients in discovery, modeling, external and prospective cohorts. During real-world testing, prediction of MRI-PTPCa demonstrated consistency with pathology and superior performance (area under the curve above 0.978; grading accuracy 89.1%) compared with clinical measures and other prediction models. This work introduces a scalable, noninvasive approach to prostate cancer diagnosis and grading, offering a robust tool to support clinical decision-making while reducing reliance on biopsies. Shao et al. developed an MRI–pathology-based foundation model to assess the pathology of prostate cancer for diagnosis and grading of tumors. The model is noninvasive and outperforms current pathological assessments.
{"title":"An MRI–pathology foundation model for noninvasive diagnosis and grading of prostate cancer","authors":"Lizhi Shao, Chao Liang, Ye Yan, Haibin Zhu, Xiaoming Jiang, Meiling Bao, Pan Zang, Xiazi Huang, Hongyu Zhou, Pei Nie, Liang Wang, Jie Li, Shudong Zhang, Shancheng Ren","doi":"10.1038/s43018-025-01041-x","DOIUrl":"10.1038/s43018-025-01041-x","url":null,"abstract":"Prostate cancer is a leading health concern for men, yet current clinical assessments of tumor aggressiveness rely on invasive procedures that often lead to inconsistencies. There remains a critical need for accurate, noninvasive diagnosis and grading methods. Here we developed a foundation model trained on multiparametric magnetic resonance imaging (MRI) and paired pathology data for noninvasive diagnosis and grading of prostate cancer. Our model, MRI-based Predicted Transformer for Prostate Cancer (MRI-PTPCa), was trained under contrastive learning on nearly 1.3 million image–pathology pairs from over 5,500 patients in discovery, modeling, external and prospective cohorts. During real-world testing, prediction of MRI-PTPCa demonstrated consistency with pathology and superior performance (area under the curve above 0.978; grading accuracy 89.1%) compared with clinical measures and other prediction models. This work introduces a scalable, noninvasive approach to prostate cancer diagnosis and grading, offering a robust tool to support clinical decision-making while reducing reliance on biopsies. Shao et al. developed an MRI–pathology-based foundation model to assess the pathology of prostate cancer for diagnosis and grading of tumors. The model is noninvasive and outperforms current pathological assessments.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 10","pages":"1621-1637"},"PeriodicalIF":28.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961810","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 : 2025-08-29DOI: 10.1038/s43018-025-01032-y
We integrated multi-omics data to construct a dynamic epigenomic atlas of colorectal cancer, identifying functional cis-regulatory elements through CRISPR interference screening. Furthermore, we developed a functionally informed polygenic risk score based on cis-regulatory element variants for risk prediction and revealed an epigenetic mechanism that drives colorectal cancer progression.
{"title":"Epigenomics and CRISPRi reveal cis-regulatory elements in colorectal cancer","authors":"","doi":"10.1038/s43018-025-01032-y","DOIUrl":"10.1038/s43018-025-01032-y","url":null,"abstract":"We integrated multi-omics data to construct a dynamic epigenomic atlas of colorectal cancer, identifying functional cis-regulatory elements through CRISPR interference screening. Furthermore, we developed a functionally informed polygenic risk score based on cis-regulatory element variants for risk prediction and revealed an epigenetic mechanism that drives colorectal cancer progression.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 11","pages":"1757-1758"},"PeriodicalIF":28.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961850","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 : 2025-08-28DOI: 10.1038/s43018-025-01005-1
Daniel Delitto, Michael T. Longaker
Cancer-associated fibroblasts represent a functionally diverse and heterogeneous entity within the solid tumor microenvironment. Mitochondrial transfer from cancer cells to fibroblasts is now shown to act as a reprogramming stimulus, driving metabolic and functional differentiation of fibroblasts to support tumor growth.
{"title":"Cancer-derived mitochondria fuel fibroblasts to become pro-tumorigenic","authors":"Daniel Delitto, Michael T. Longaker","doi":"10.1038/s43018-025-01005-1","DOIUrl":"10.1038/s43018-025-01005-1","url":null,"abstract":"Cancer-associated fibroblasts represent a functionally diverse and heterogeneous entity within the solid tumor microenvironment. Mitochondrial transfer from cancer cells to fibroblasts is now shown to act as a reprogramming stimulus, driving metabolic and functional differentiation of fibroblasts to support tumor growth.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 10","pages":"1615-1616"},"PeriodicalIF":28.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961843","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 : 2025-08-28DOI: 10.1038/s43018-025-01038-6
Michael Cangkrama, Huan Liu, Xiaoyu Wu, Josephine Yates, James Whipman, Christoph G. Gäbelein, Mai Matsushita, Luca Ferrarese, Sibilla Sander, Francesc Castro-Giner, Simran Asawa, Magdalena K. Sznurkowska, Manfred Kopf, Jörn Dengjel, Valentina Boeva, Nicola Aceto, Julia A. Vorholt, Sabine Werner
Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that commonly support cancer development and progression. Here we show that different cancer cells transfer mitochondria to fibroblasts in cocultures and xenograft tumors, thereby inducing protumorigenic CAF features. Transplantation of functional mitochondria from cancer cells induces metabolic alterations in fibroblasts, expression of CAF markers and release of a protumorigenic secretome and matrisome. These features promote tumor formation in preclinical mouse models. Mechanistically, the mitochondrial transfer requires the mitochondrial trafficking protein MIRO2. Its depletion in cancer cells suppresses mitochondrial transfer and inhibits CAF differentiation and tumor growth. The clinical relevance of these findings is reflected by the overexpression of MIRO2 in tumor cells at the leading edge of epithelial skin cancers. These results identify mitochondrial transfer from cancer cells to fibroblasts as a driver of tumorigenesis and provide a rationale for targeting MIRO2 and mitochondrial transfer in different malignancies. Cangkrama et al. show that tumor cells from various cancer types use the mitochondrial trafficking protein MIRO2 and nanotubes to transfer mitochondria into surrounding fibroblasts, thereby inducing cancer-associated fibroblast differentiation and subsequent tumor growth.
{"title":"MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation","authors":"Michael Cangkrama, Huan Liu, Xiaoyu Wu, Josephine Yates, James Whipman, Christoph G. Gäbelein, Mai Matsushita, Luca Ferrarese, Sibilla Sander, Francesc Castro-Giner, Simran Asawa, Magdalena K. Sznurkowska, Manfred Kopf, Jörn Dengjel, Valentina Boeva, Nicola Aceto, Julia A. Vorholt, Sabine Werner","doi":"10.1038/s43018-025-01038-6","DOIUrl":"10.1038/s43018-025-01038-6","url":null,"abstract":"Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that commonly support cancer development and progression. Here we show that different cancer cells transfer mitochondria to fibroblasts in cocultures and xenograft tumors, thereby inducing protumorigenic CAF features. Transplantation of functional mitochondria from cancer cells induces metabolic alterations in fibroblasts, expression of CAF markers and release of a protumorigenic secretome and matrisome. These features promote tumor formation in preclinical mouse models. Mechanistically, the mitochondrial transfer requires the mitochondrial trafficking protein MIRO2. Its depletion in cancer cells suppresses mitochondrial transfer and inhibits CAF differentiation and tumor growth. The clinical relevance of these findings is reflected by the overexpression of MIRO2 in tumor cells at the leading edge of epithelial skin cancers. These results identify mitochondrial transfer from cancer cells to fibroblasts as a driver of tumorigenesis and provide a rationale for targeting MIRO2 and mitochondrial transfer in different malignancies. Cangkrama et al. show that tumor cells from various cancer types use the mitochondrial trafficking protein MIRO2 and nanotubes to transfer mitochondria into surrounding fibroblasts, thereby inducing cancer-associated fibroblast differentiation and subsequent tumor growth.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 10","pages":"1714-1733"},"PeriodicalIF":28.5,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01038-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961865","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 : 2025-08-27DOI: 10.1038/s43018-025-01024-y
Ronald A. DePinho
Ron DePinho received his MD from the Albert Einstein College of Medicine and completed his medical and postdoctoral training at Columbia University. He was the founding director of the Belfer Center at the Dana-Farber Cancer Institute. As president of the University of Texas MD Anderson Cancer Center, he launched the Cancer Moonshot initiative. He currently serves as a professor of cancer biology at the MD Anderson Cancer Center and was elected to the National Academies of Sciences and Medicine. He is the co-founder of several biotech companies and an advocate for innovation-driven healthspan solutions for the underserved.
Ron DePinho在爱因斯坦医学院获得医学博士学位，并在哥伦比亚大学完成了医学和博士后培训。他是丹娜-法伯癌症研究所贝尔弗中心的创始主任。作为德克萨斯大学MD安德森癌症中心的主席，他发起了癌症登月计划。他目前担任MD安德森癌症中心的癌症生物学教授，并当选为美国国家科学院和医学院院士。他是几家生物技术公司的联合创始人，并倡导为服务不足的人群提供创新驱动的健康解决方案。
{"title":"Telescopes, telomeres and turning points","authors":"Ronald A. DePinho","doi":"10.1038/s43018-025-01024-y","DOIUrl":"10.1038/s43018-025-01024-y","url":null,"abstract":"Ron DePinho received his MD from the Albert Einstein College of Medicine and completed his medical and postdoctoral training at Columbia University. He was the founding director of the Belfer Center at the Dana-Farber Cancer Institute. As president of the University of Texas MD Anderson Cancer Center, he launched the Cancer Moonshot initiative. He currently serves as a professor of cancer biology at the MD Anderson Cancer Center and was elected to the National Academies of Sciences and Medicine. He is the co-founder of several biotech companies and an advocate for innovation-driven healthspan solutions for the underserved.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 9","pages":"1479-1479"},"PeriodicalIF":28.5,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961813","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}
The tumor microenvironment evolves during tumor development and influences the cells in the microenvironment to orchestrate a supportive environment for tumor growth. Here we collected 4,483,367 cells across 36 cancer types and constructed a pan-cancer resource named TabulaTIME. Our integrated analyses reveal that CTHRC1 is a hallmark of extracellular matrix-related cancer-associated fibroblasts (CAFs) that are enriched in different cancer types. Spatiotemporal analyses further indicated that CTHRC1+ CAFs are located at the leading edge between the malignant and normal regions, potentially preventing immune infiltration. Moreover, we identified that SLPI+ macrophages exhibit profibrotic-associated phenotypes and colocalize with CTHRC1+ CAFs to form unique spatial ecotypes. Finally, we demonstrated that TabulaTIME can be used to analyze tumor ecotype composition and can serve as a reference for cell-type annotation. This work establishes a comprehensive single-cell landscape of the heterogenous TME and offers a potential therapeutic strategy for targeting the profibrotic ecotype in cancer treatment. Han et al. present TabulaTIME, a multicancer scRNA-seq resource, and report enrichment of extracellular matrix-related CTHRC1+ cancer-associated fibroblasts in proximity to SLPI+ macrophages, creating a profibrotic ecotype associated with tumor immunity.
{"title":"Spatiotemporal analyses of the pan-cancer single-cell landscape reveal widespread profibrotic ecotypes associated with tumor immunity","authors":"Ya Han, Lele Zhang, Dongqing Sun, Guangxu Cao, Yuting Wang, Jiali Yue, Junjie Hu, Zhonghua Dong, Fang Li, Taiwen Li, Peng Zhang, Qiu Wu, Chenfei Wang","doi":"10.1038/s43018-025-01039-5","DOIUrl":"10.1038/s43018-025-01039-5","url":null,"abstract":"The tumor microenvironment evolves during tumor development and influences the cells in the microenvironment to orchestrate a supportive environment for tumor growth. Here we collected 4,483,367 cells across 36 cancer types and constructed a pan-cancer resource named TabulaTIME. Our integrated analyses reveal that CTHRC1 is a hallmark of extracellular matrix-related cancer-associated fibroblasts (CAFs) that are enriched in different cancer types. Spatiotemporal analyses further indicated that CTHRC1+ CAFs are located at the leading edge between the malignant and normal regions, potentially preventing immune infiltration. Moreover, we identified that SLPI+ macrophages exhibit profibrotic-associated phenotypes and colocalize with CTHRC1+ CAFs to form unique spatial ecotypes. Finally, we demonstrated that TabulaTIME can be used to analyze tumor ecotype composition and can serve as a reference for cell-type annotation. This work establishes a comprehensive single-cell landscape of the heterogenous TME and offers a potential therapeutic strategy for targeting the profibrotic ecotype in cancer treatment. Han et al. present TabulaTIME, a multicancer scRNA-seq resource, and report enrichment of extracellular matrix-related CTHRC1+ cancer-associated fibroblasts in proximity to SLPI+ macrophages, creating a profibrotic ecotype associated with tumor immunity.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 11","pages":"1880-1898"},"PeriodicalIF":28.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01039-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961818","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}
Genetic variants associated with colorectal cancer (CRC) are primarily noncoding and reside in cis-regulatory elements (CREs), yet their underlying mechanisms remain elusive. Here we established a dynamic epigenetic atlas using multiomics data from 533 colorectal tissues spanning normal to advanced adenoma to cancer, identifying 7,492 differential CREs linked to 5,490 target genes. High-throughput CRISPR interference screening revealed 265 functional CREs involved in CRC cell proliferation. A polygenic risk score (PRS) based on functional CRE variants effectively predicted CRC and precancerous lesions among 476,770 individuals. Notably, the functional variant rs10871066 was significantly associated with increased risk of precancerous lesions and CRC (odds ratio = 1.27, P = 1.03 × 10−13). Mechanistically, rs10871066 triggers silencer-to-enhancer switching mediated by FOXP1 and TCF7L2, distally upregulating KLF5 to activate oncogenic pathways and PIBF1 to suppress natural killer cell cytotoxicity. Our study provides a comprehensive resource of dynamic epigenomic atlas, a functionally informed PRS for risk prediction and insights into epigenetic mechanisms underlying CRC development. Lu et al. characterize cis-regulatory element dynamics at different stages of colorectal cancer progression and identify a functional variant associated with increased colorectal cancer risk because of selective transcription factor binding.
{"title":"Characterization of cis-regulatory elements and functional variants in colorectal cancer using epigenomics and CRISPRi screenings","authors":"Zequn Lu, Can Chen, Heng Zhang, Bin Li, Yizhuo Liu, Jiayi Guo, Runying Xu, Ke Shi, Qianying Ma, Ming Zhang, Yimin Cai, Jinyu Huang, Hui Geng, Linyun Fan, Caibo Ning, Yanmin Li, Shuoni Chen, Wen Tian, Kexin Hu, Haijie Li, Xiaojun Yang, Chaoqun Huang, Yongchang Wei, Xu Zhu, Xiangpan Li, Zhen Xiong, Ming Cai, Xiaoyang Wang, Shaokai Zhang, Hongda Chen, Min Dai, Kun Chen, Mingjuan Jin, Meng Jin, Ying Zhu, Jianbo Tian, Xiaoping Miao","doi":"10.1038/s43018-025-01031-z","DOIUrl":"10.1038/s43018-025-01031-z","url":null,"abstract":"Genetic variants associated with colorectal cancer (CRC) are primarily noncoding and reside in cis-regulatory elements (CREs), yet their underlying mechanisms remain elusive. Here we established a dynamic epigenetic atlas using multiomics data from 533 colorectal tissues spanning normal to advanced adenoma to cancer, identifying 7,492 differential CREs linked to 5,490 target genes. High-throughput CRISPR interference screening revealed 265 functional CREs involved in CRC cell proliferation. A polygenic risk score (PRS) based on functional CRE variants effectively predicted CRC and precancerous lesions among 476,770 individuals. Notably, the functional variant rs10871066 was significantly associated with increased risk of precancerous lesions and CRC (odds ratio = 1.27, P = 1.03 × 10−13). Mechanistically, rs10871066 triggers silencer-to-enhancer switching mediated by FOXP1 and TCF7L2, distally upregulating KLF5 to activate oncogenic pathways and PIBF1 to suppress natural killer cell cytotoxicity. Our study provides a comprehensive resource of dynamic epigenomic atlas, a functionally informed PRS for risk prediction and insights into epigenetic mechanisms underlying CRC development. Lu et al. characterize cis-regulatory element dynamics at different stages of colorectal cancer progression and identify a functional variant associated with increased colorectal cancer risk because of selective transcription factor binding.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 11","pages":"1777-1799"},"PeriodicalIF":28.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961855","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}
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