Pub Date : 2025-11-11DOI: 10.1038/s43018-025-01057-3
Relapse after CAR T cell therapy is often caused by tumors that have low levels of the target antigen. By engineering a membrane-tethered version of the signaling adaptor SLP-76, we improved the ability of CAR T cells to respond to antigen-low tumors. This restored CAR T cell function in multiple preclinical models and offers a potential strategy to overcome this common form of resistance.
CAR - T细胞治疗后的复发通常是由目标抗原水平低的肿瘤引起的。通过设计信号转接器SLP-76的膜系版本，我们提高了CAR - T细胞对低抗原肿瘤的反应能力。这在多个临床前模型中恢复了CAR - T细胞的功能，并提供了克服这种常见抵抗形式的潜在策略。
{"title":"Enhancing CAR sensitivity through engineering of proximal signaling molecules","authors":"","doi":"10.1038/s43018-025-01057-3","DOIUrl":"10.1038/s43018-025-01057-3","url":null,"abstract":"Relapse after CAR T cell therapy is often caused by tumors that have low levels of the target antigen. By engineering a membrane-tethered version of the signaling adaptor SLP-76, we improved the ability of CAR T cells to respond to antigen-low tumors. This restored CAR T cell function in multiple preclinical models and offers a potential strategy to overcome this common form of resistance.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 12","pages":"1936-1937"},"PeriodicalIF":28.5,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145496120","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 : 2025-11-06DOI: 10.1038/s43018-025-01065-3
Jing Han, Xiaoman Lu, Mengmeng Guo, Ruizhe He, Meilian Zhuo, Saisai Wang, Yong Li, Xiangzheng Liu, Di Zou, Jiacheng Wang, Jiangjiao Mao, Qian Chen, Xia Wang, Junya Peng, Wei Xie, Charles J. David, Mo Chen
Acute pancreatitis-induced acinar-to-ductal metaplasia involves global chromatin remodeling and contributes to normal tissue regeneration. Oncogenic KRAS hijacks this process to promote PDAC formation. Here we show that regeneration and KRASG12D-driven oncogenesis can be decoupled from tissue regeneration through a chromatin remodeler, SMARCA5. We show that SMARCA5 maintains KRASG12D-dependent chromatin accessibility at regions specifically required for malignancy, without affecting chromatin opening that occurs during normal regeneration. Without SMARCA5, regeneration can be restored in the presence of KRASG12D. Mechanistically, regeneration-related or malignancy-related chromatin remodeling activities occur in a time-sensitive manner. The activity of SMARCA5 is controlled spatiotemporally by transcription factor RUNX1, which only accumulates at sufficient levels with sustained MAPK signals. We further show that inhibition of the SMARCA5-containing NoRC complex specifically inhibits the growth of PDAC organoid but not that of normal tissue derived from patients. Han et al. show that SMARCA5 is required for the sustained expression of genes required for malignancy in pancreatic cells with mutant KRAS. Inhibiting SMARCA5 activity prevents malignant transformation while maintaining pancreatic regeneration.
{"title":"Spatiotemporal control of SMARCA5 by a MAPK–RUNX1 axis distinguishes mutant KRAS-driven pancreatic malignancy from tissue regeneration","authors":"Jing Han, Xiaoman Lu, Mengmeng Guo, Ruizhe He, Meilian Zhuo, Saisai Wang, Yong Li, Xiangzheng Liu, Di Zou, Jiacheng Wang, Jiangjiao Mao, Qian Chen, Xia Wang, Junya Peng, Wei Xie, Charles J. David, Mo Chen","doi":"10.1038/s43018-025-01065-3","DOIUrl":"10.1038/s43018-025-01065-3","url":null,"abstract":"Acute pancreatitis-induced acinar-to-ductal metaplasia involves global chromatin remodeling and contributes to normal tissue regeneration. Oncogenic KRAS hijacks this process to promote PDAC formation. Here we show that regeneration and KRASG12D-driven oncogenesis can be decoupled from tissue regeneration through a chromatin remodeler, SMARCA5. We show that SMARCA5 maintains KRASG12D-dependent chromatin accessibility at regions specifically required for malignancy, without affecting chromatin opening that occurs during normal regeneration. Without SMARCA5, regeneration can be restored in the presence of KRASG12D. Mechanistically, regeneration-related or malignancy-related chromatin remodeling activities occur in a time-sensitive manner. The activity of SMARCA5 is controlled spatiotemporally by transcription factor RUNX1, which only accumulates at sufficient levels with sustained MAPK signals. We further show that inhibition of the SMARCA5-containing NoRC complex specifically inhibits the growth of PDAC organoid but not that of normal tissue derived from patients. Han et al. show that SMARCA5 is required for the sustained expression of genes required for malignancy in pancreatic cells with mutant KRAS. Inhibiting SMARCA5 activity prevents malignant transformation while maintaining pancreatic regeneration.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"43-59"},"PeriodicalIF":28.5,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459267","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 : 2025-11-01DOI: 10.1038/s43018-025-01058-2
Sijia Gu, Qiyu Luo, Yalei Zhang, Ling Qian, Kun Chen, Fei Liang, Yudi Hu, Runye Zhou, Yating Wang, Jingjing Liu, Zhouyu Ning, Litao Xu, Zhiqiang Meng, Ye Li, Peng Wang
Treatment options for advanced or metastatic intrahepatic cholangiocarcinoma (ICC) are limited. In this single-arm, phase 2 trial (CASTLE-01, NCT05010668 ), 28 participants with advanced or metastatic ICC who have progressed after chemotherapy were treated with cryoablation, followed by anti-PD1 sintilimab (200 mg every 3 weeks) plus lenvatinib (8–12 mg per day) 2 weeks later. The objective response rate assessed by Response Evaluation Criteria in Solid Tumors version 1.1 was 75.0% (95% confidence interval (CI): 59–91%), meeting the prespecified primary endpoint. Secondary endpoints of disease control rate, median progression-free survival and overall survival were respectively 100% (95% CI: 100–100%), 16.8 months (95% CI: 11.5–not reached (NR)) and 25.4 months (95% CI: 13.3–NR). Treatment was well tolerated. Post hoc multiomics analysis of paired pretreatment and on-treatment tumor biopsies suggested that cryoablation increased the tumor immunogenicity and dendritic cell activation, followed by triggering continuous replenishment of intratumoral CD8+PD1hi effectors from peripheral blood. The addition of lenvatinib transitioned endothelial cells into inflamed venules to boost lymphocyte influx and targeted tumor stroma to promote CD8+PD1hi effectors penetrating into tumor cell nests. Therefore, cryoablation combined with sintilimab plus lenvatinib represents a promising approach for the treatment of advanced or metastatic ICC. These findings also support the notion that cryoablation may trigger abscopal antitumor immunity in ICC when combined with lenvatinib and PD1 blockade. ClinicalTrials.gov registration: NCT05010668 . Wang and colleagues report the clinical results and immunological correlates of a phase 2 clinical trial of cryoablation plus lenvatinib and sintilimab in persons with advanced or metastatic intrahepatic cholangiocarcinoma.
{"title":"Cryoablation plus sintilimab and lenvatinib in advanced or metastatic intrahepatic cholangiocarcinoma: a phase 2 trial","authors":"Sijia Gu, Qiyu Luo, Yalei Zhang, Ling Qian, Kun Chen, Fei Liang, Yudi Hu, Runye Zhou, Yating Wang, Jingjing Liu, Zhouyu Ning, Litao Xu, Zhiqiang Meng, Ye Li, Peng Wang","doi":"10.1038/s43018-025-01058-2","DOIUrl":"10.1038/s43018-025-01058-2","url":null,"abstract":"Treatment options for advanced or metastatic intrahepatic cholangiocarcinoma (ICC) are limited. In this single-arm, phase 2 trial (CASTLE-01, NCT05010668 ), 28 participants with advanced or metastatic ICC who have progressed after chemotherapy were treated with cryoablation, followed by anti-PD1 sintilimab (200 mg every 3 weeks) plus lenvatinib (8–12 mg per day) 2 weeks later. The objective response rate assessed by Response Evaluation Criteria in Solid Tumors version 1.1 was 75.0% (95% confidence interval (CI): 59–91%), meeting the prespecified primary endpoint. Secondary endpoints of disease control rate, median progression-free survival and overall survival were respectively 100% (95% CI: 100–100%), 16.8 months (95% CI: 11.5–not reached (NR)) and 25.4 months (95% CI: 13.3–NR). Treatment was well tolerated. Post hoc multiomics analysis of paired pretreatment and on-treatment tumor biopsies suggested that cryoablation increased the tumor immunogenicity and dendritic cell activation, followed by triggering continuous replenishment of intratumoral CD8+PD1hi effectors from peripheral blood. The addition of lenvatinib transitioned endothelial cells into inflamed venules to boost lymphocyte influx and targeted tumor stroma to promote CD8+PD1hi effectors penetrating into tumor cell nests. Therefore, cryoablation combined with sintilimab plus lenvatinib represents a promising approach for the treatment of advanced or metastatic ICC. These findings also support the notion that cryoablation may trigger abscopal antitumor immunity in ICC when combined with lenvatinib and PD1 blockade. ClinicalTrials.gov registration: NCT05010668 . Wang and colleagues report the clinical results and immunological correlates of a phase 2 clinical trial of cryoablation plus lenvatinib and sintilimab in persons with advanced or metastatic intrahepatic cholangiocarcinoma.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"7 1","pages":"60-79"},"PeriodicalIF":28.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01058-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427009","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 : 2025-10-27DOI: 10.1038/s43018-025-01061-7
Yijie Tao, Shulei Yin, Kai Wei, Liyuan Zhao, Yani Cui, Chunzhen Li, Yunyang Wu, Panpan Hu, Shenhui Yin, Likun Cui, Yunyan Zhang, Yixian He, Shu Yu, Jie Chen, Shaoteng Lu, Guifang Qiu, Mengqi Song, Siqi Yang, Qianshan Hou, Yiquan Xue, Chen Qian, Sheng Xu, Yizhi Yu, Zui Zou
Systemic therapy is the optimal choice for individuals with unresectable or advanced hepatocellular carcinoma (HCC). However its effectiveness is constrained by resistance. Ferroptosis is a unique form of regulated cell death and plays an essential role in HCC systemic therapy. Here we identified that secernin-1 (SCRN1) was closely associated with ferroptosis resistance and poor prognosis in HCC. Specifically, high expression of SCRN1 enhances the interaction of phosphokinase serine/threonine kinase 38 (STK38) and glutathione peroxidase 4 (GPX4) to promote the phosphorylation of GPX4 at S45. This phosphorylation impairs heat shock protein family A member 8 (HSC70) recognition and degradation of GPX4 by chaperone-mediated autophagy, which further alleviates lipid peroxidation and ferroptosis. Our findings reveal a critical mechanism by which tumor cells antagonize ferroptosis through enhanced GPX4 phosphorylation and provide potential targets and strategies for HCC treatment. Tao et al. show that SCRN1 acts as a scaffold to facilitate GPX4 phosphorylation by STK38, thereby preventing chaperone-mediated autophagy of GPX4 and subsequent ferroptosis in patient-derived organoids and mouse models for hepatocellular carcinoma.
{"title":"SCRN1 confers hepatocellular carcinoma resistance to ferroptosis by stabilizing GPX4 via STK38-mediated phosphorylation","authors":"Yijie Tao, Shulei Yin, Kai Wei, Liyuan Zhao, Yani Cui, Chunzhen Li, Yunyang Wu, Panpan Hu, Shenhui Yin, Likun Cui, Yunyan Zhang, Yixian He, Shu Yu, Jie Chen, Shaoteng Lu, Guifang Qiu, Mengqi Song, Siqi Yang, Qianshan Hou, Yiquan Xue, Chen Qian, Sheng Xu, Yizhi Yu, Zui Zou","doi":"10.1038/s43018-025-01061-7","DOIUrl":"10.1038/s43018-025-01061-7","url":null,"abstract":"Systemic therapy is the optimal choice for individuals with unresectable or advanced hepatocellular carcinoma (HCC). However its effectiveness is constrained by resistance. Ferroptosis is a unique form of regulated cell death and plays an essential role in HCC systemic therapy. Here we identified that secernin-1 (SCRN1) was closely associated with ferroptosis resistance and poor prognosis in HCC. Specifically, high expression of SCRN1 enhances the interaction of phosphokinase serine/threonine kinase 38 (STK38) and glutathione peroxidase 4 (GPX4) to promote the phosphorylation of GPX4 at S45. This phosphorylation impairs heat shock protein family A member 8 (HSC70) recognition and degradation of GPX4 by chaperone-mediated autophagy, which further alleviates lipid peroxidation and ferroptosis. Our findings reveal a critical mechanism by which tumor cells antagonize ferroptosis through enhanced GPX4 phosphorylation and provide potential targets and strategies for HCC treatment. Tao et al. show that SCRN1 acts as a scaffold to facilitate GPX4 phosphorylation by STK38, thereby preventing chaperone-mediated autophagy of GPX4 and subsequent ferroptosis in patient-derived organoids and mouse models for hepatocellular carcinoma.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 12","pages":"1976-1993"},"PeriodicalIF":28.5,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145378071","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 : 2025-10-23DOI: 10.1038/s43018-025-01056-4
Maria Caterina Rotiroti, Aidan M. Tousley, Hoyin Chu, Marco Herrera-Barrera, Antigoni Manousopoulou, Won-Ju Kim, Yajie Yin, Thomas Spencer Parish, Aniela Mitchell, Malcolm Holterhus, Lea Wenting Rysavy, Guillermo Nicolas Dalton, Katherine Ann Freitas, Gernot Kaber, Korbinian N. Kropp, Christopher A. Klebanoff, Ansuman T. Satpathy, Leo D. Wang, Caleb A. Lareau, Robbie G. Majzner
Chimeric antigen receptor (CAR) T cells can mediate durable complete responses in individuals with certain hematologic malignancies, but antigen downregulation is a common mechanism of resistance. Although the native T cell receptor can respond to very low levels of antigen, engineered CARs cannot, likely due to inefficient recruitment of downstream proximal signaling molecules. We developed a platform that endows CAR T cells with the ability to kill antigen-low cancer cells consisting of a membrane-tethered version of the cytosolic signaling adaptor molecule SLP-76 (MT-SLP-76). MT-SLP-76 can be expressed alongside any CAR to lower its activation threshold, overcoming antigen-low escape in multiple xenograft models. Mechanistically, MT-SLP-76 amplifies CAR signaling through recruitment of ITK and PLCγ1. MT-SLP-76 was designed based on biologic principles to render CAR T cell therapies less susceptible to antigen downregulation and is poised for clinical development to overcome this common mechanism of resistance. Majzner and colleagues show that engineering T cells with a membrane-tethered version of the signaling adaptor molecule SLP-76 alongside a chimeric antigen receptor (CAR) enhances CAR T cell activity against low-antigen-density tumors.
{"title":"Engineering T cells with a membrane-tethered version of SLP-76 overcomes antigen-low resistance to CAR T cell therapy","authors":"Maria Caterina Rotiroti, Aidan M. Tousley, Hoyin Chu, Marco Herrera-Barrera, Antigoni Manousopoulou, Won-Ju Kim, Yajie Yin, Thomas Spencer Parish, Aniela Mitchell, Malcolm Holterhus, Lea Wenting Rysavy, Guillermo Nicolas Dalton, Katherine Ann Freitas, Gernot Kaber, Korbinian N. Kropp, Christopher A. Klebanoff, Ansuman T. Satpathy, Leo D. Wang, Caleb A. Lareau, Robbie G. Majzner","doi":"10.1038/s43018-025-01056-4","DOIUrl":"10.1038/s43018-025-01056-4","url":null,"abstract":"Chimeric antigen receptor (CAR) T cells can mediate durable complete responses in individuals with certain hematologic malignancies, but antigen downregulation is a common mechanism of resistance. Although the native T cell receptor can respond to very low levels of antigen, engineered CARs cannot, likely due to inefficient recruitment of downstream proximal signaling molecules. We developed a platform that endows CAR T cells with the ability to kill antigen-low cancer cells consisting of a membrane-tethered version of the cytosolic signaling adaptor molecule SLP-76 (MT-SLP-76). MT-SLP-76 can be expressed alongside any CAR to lower its activation threshold, overcoming antigen-low escape in multiple xenograft models. Mechanistically, MT-SLP-76 amplifies CAR signaling through recruitment of ITK and PLCγ1. MT-SLP-76 was designed based on biologic principles to render CAR T cell therapies less susceptible to antigen downregulation and is poised for clinical development to overcome this common mechanism of resistance. Majzner and colleagues show that engineering T cells with a membrane-tethered version of the signaling adaptor molecule SLP-76 alongside a chimeric antigen receptor (CAR) enhances CAR T cell activity against low-antigen-density tumors.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 12","pages":"1940-1954"},"PeriodicalIF":28.5,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01056-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355574","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 : 2025-10-23DOI: 10.1038/s43018-025-01059-1
Junyu Xiang, Yuanli Ni, Jiajun Yu, Hui Sun, Zhiyun Gu, Ziyong Li, Tongwang Yang, Juan Feng, Li Su, Limei Liu, Jiatao Li, Jesus Prieto, Matías A. Ávila, Juanjuan Shan, Na Zhuang, Cheng Qian
Cancers often originate from precursor cells within an inflamed microenvironment; however, the mechanisms by which these precursors manipulate the niche to promote tumorigenesis remain unclear. By combining single-cell and spatial transcriptomic analyses of precancerous lesions in hepatocellular carcinoma, here we show that elevated myocyte enhancer factor 2D (MEF2D)-expressing cancer precursors reprogram liver-resident macrophages, Kupffer cells (KCs), to create a growth-supportive environment. MEF2D levels induce an oncogenic and secretory phenotype in these precursors by epigenetic reprogramming, which is crucial for tumor initiation in murine models and human samples. This results in a KC-rich niche through paracrine activation of neuropilin 1 (NRP1) signaling on stem-like KC subtype-2 (KC2), driving its differentiation into KC subtype-1 (KC1)-like cells. Pro-inflammatory KC1s release cytokines, particularly IL-6, to enhance an MEF2D-mediated tumor-promoting program in nearby cancer precursors. Targeting NRP1 signaling disrupts the KC2-to-KC1-like differentiation and reduces niche inflammation, thereby inhibiting liver tumorigenesis in male mice. Thus, preventing aberrant KC subtype conversion in the precancerous microenvironment is a viable strategy for early cancer prevention. Qian and colleagues show that MEF2D+ cancer precursors reprogram liver-resident Kupffer cells to create a microenvironment supporting liver tumorigenesis.
{"title":"MEF2D-expressing cancer precursors reprogram tissue-resident macrophages to support liver tumorigenesis","authors":"Junyu Xiang, Yuanli Ni, Jiajun Yu, Hui Sun, Zhiyun Gu, Ziyong Li, Tongwang Yang, Juan Feng, Li Su, Limei Liu, Jiatao Li, Jesus Prieto, Matías A. Ávila, Juanjuan Shan, Na Zhuang, Cheng Qian","doi":"10.1038/s43018-025-01059-1","DOIUrl":"10.1038/s43018-025-01059-1","url":null,"abstract":"Cancers often originate from precursor cells within an inflamed microenvironment; however, the mechanisms by which these precursors manipulate the niche to promote tumorigenesis remain unclear. By combining single-cell and spatial transcriptomic analyses of precancerous lesions in hepatocellular carcinoma, here we show that elevated myocyte enhancer factor 2D (MEF2D)-expressing cancer precursors reprogram liver-resident macrophages, Kupffer cells (KCs), to create a growth-supportive environment. MEF2D levels induce an oncogenic and secretory phenotype in these precursors by epigenetic reprogramming, which is crucial for tumor initiation in murine models and human samples. This results in a KC-rich niche through paracrine activation of neuropilin 1 (NRP1) signaling on stem-like KC subtype-2 (KC2), driving its differentiation into KC subtype-1 (KC1)-like cells. Pro-inflammatory KC1s release cytokines, particularly IL-6, to enhance an MEF2D-mediated tumor-promoting program in nearby cancer precursors. Targeting NRP1 signaling disrupts the KC2-to-KC1-like differentiation and reduces niche inflammation, thereby inhibiting liver tumorigenesis in male mice. Thus, preventing aberrant KC subtype conversion in the precancerous microenvironment is a viable strategy for early cancer prevention. Qian and colleagues show that MEF2D+ cancer precursors reprogram liver-resident Kupffer cells to create a microenvironment supporting liver tumorigenesis.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 12","pages":"1955-1975"},"PeriodicalIF":28.5,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355558","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 : 2025-10-10DOI: 10.1038/s43018-025-01064-4
Kar Wei Chin, Wan-Qin Chong, Boon Cher Goh, Brigette B. Y. Ma
{"title":"Author Correction: Evolving landscape of nasopharyngeal carcinoma therapy","authors":"Kar Wei Chin, Wan-Qin Chong, Boon Cher Goh, Brigette B. Y. Ma","doi":"10.1038/s43018-025-01064-4","DOIUrl":"10.1038/s43018-025-01064-4","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 11","pages":"1899-1899"},"PeriodicalIF":28.5,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43018-025-01064-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275204","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 : 2025-10-10DOI: 10.1038/s43018-025-01048-4
Amy C. Gladstein, David M. Feldser
Little is known about how mutations in genes encoding tumor suppressors influence metastatic site selection and whether sustained inactivation of such genes influences tumor maintenance at these sites. A new study shows that restoration of Smad4 expression in extant pancreatic metastases has anti-tumor effects in the liver but pro-tumor effects in the lungs.
{"title":"Primary tumor chromatin landscape governs metastatic organotropism","authors":"Amy C. Gladstein, David M. Feldser","doi":"10.1038/s43018-025-01048-4","DOIUrl":"10.1038/s43018-025-01048-4","url":null,"abstract":"Little is known about how mutations in genes encoding tumor suppressors influence metastatic site selection and whether sustained inactivation of such genes influences tumor maintenance at these sites. A new study shows that restoration of Smad4 expression in extant pancreatic metastases has anti-tumor effects in the liver but pro-tumor effects in the lungs.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 11","pages":"1755-1756"},"PeriodicalIF":28.5,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275256","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 : 2025-10-07DOI: 10.1038/s43018-025-01053-7
William Zhao, Thinh T. Nguyen, Atharva Bhagwat, Akhil Kumar, Bruno Giotti, Benjamin Kepecs, Jason L. Weirather, Navin R. Mahadevan, Asa Segerstolpe, Komal Dolasia, Jamshid Abdul-Ghafar, Naomi R. Besson, Stephanie M. Jones, Brian Y. Soong, Chendi Li, Sebastien Vigneau, Michal Slyper, Isaac Wakiro, Mei-Ju Su, Karla Helvie, Allison Frangieh, Judit Jane-Valbuena, Orr Ashenberg, Mark Awad, Asaf Rotem, Raphael Bueno, Orit Rozenblatt-Rosen, Kathleen Pfaff, Scott Rodig, Aaron N. Hata, Aviv Regev, Bruce E. Johnson, Alexander M. Tsankov
Tumor protein p53 (TP53) is the most frequently mutated gene across many cancers and is associated with shorter overall survival in lung adenocarcinoma (LUAD). Here, to define how TP53 mutations affect the LUAD tumor microenvironment (TME), we constructed a multiomic cellular and spatial atlas of 23 treatment-naive human lung tumors. We found that TP53-mutant malignant cells lose alveolar identity and upregulate highly proliferative and entropic gene expression programs consistently across LUAD tumors from resectable clinical samples, genetically engineered mouse models, and cell lines harboring a wide spectrum of TP53 mutations. We further identified a multicellular tumor niche composed of SPP1+ macrophages and collagen-expressing fibroblasts that coincides with hypoxic, prometastatic expression programs in TP53-mutant tumors. Spatially correlated angiostatic and immune checkpoint interactions, including CD274–PDCD1 and PVR–TIGIT, are also enriched in TP53-mutant LUAD tumors and likely engender a more favorable response to checkpoint blockade therapy. Our systematic approach can be used to investigate genotype-associated TMEs in other cancers. Zhao et al. used single-cell and spatial multiomics data analysis of human and mouse lung adenocarcinoma tumors and cell lines to reveal TP53 mutation-associated changes in cancer cells and their microenvironment.
{"title":"A cellular and spatial atlas of TP53-associated tissue remodeling defines a multicellular tumor ecosystem in lung adenocarcinoma","authors":"William Zhao, Thinh T. Nguyen, Atharva Bhagwat, Akhil Kumar, Bruno Giotti, Benjamin Kepecs, Jason L. Weirather, Navin R. Mahadevan, Asa Segerstolpe, Komal Dolasia, Jamshid Abdul-Ghafar, Naomi R. Besson, Stephanie M. Jones, Brian Y. Soong, Chendi Li, Sebastien Vigneau, Michal Slyper, Isaac Wakiro, Mei-Ju Su, Karla Helvie, Allison Frangieh, Judit Jane-Valbuena, Orr Ashenberg, Mark Awad, Asaf Rotem, Raphael Bueno, Orit Rozenblatt-Rosen, Kathleen Pfaff, Scott Rodig, Aaron N. Hata, Aviv Regev, Bruce E. Johnson, Alexander M. Tsankov","doi":"10.1038/s43018-025-01053-7","DOIUrl":"10.1038/s43018-025-01053-7","url":null,"abstract":"Tumor protein p53 (TP53) is the most frequently mutated gene across many cancers and is associated with shorter overall survival in lung adenocarcinoma (LUAD). Here, to define how TP53 mutations affect the LUAD tumor microenvironment (TME), we constructed a multiomic cellular and spatial atlas of 23 treatment-naive human lung tumors. We found that TP53-mutant malignant cells lose alveolar identity and upregulate highly proliferative and entropic gene expression programs consistently across LUAD tumors from resectable clinical samples, genetically engineered mouse models, and cell lines harboring a wide spectrum of TP53 mutations. We further identified a multicellular tumor niche composed of SPP1+ macrophages and collagen-expressing fibroblasts that coincides with hypoxic, prometastatic expression programs in TP53-mutant tumors. Spatially correlated angiostatic and immune checkpoint interactions, including CD274–PDCD1 and PVR–TIGIT, are also enriched in TP53-mutant LUAD tumors and likely engender a more favorable response to checkpoint blockade therapy. Our systematic approach can be used to investigate genotype-associated TMEs in other cancers. Zhao et al. used single-cell and spatial multiomics data analysis of human and mouse lung adenocarcinoma tumors and cell lines to reveal TP53 mutation-associated changes in cancer cells and their microenvironment.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"6 11","pages":"1857-1879"},"PeriodicalIF":28.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244765","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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