Cancer Cell最新文献_第10页

Dendritic cell redundancy enables priming of anti-tumor CD4⁺ T cells in pancreatic cancer. 树突状细胞冗余能够在胰腺癌中启动抗肿瘤CD4+ T细胞。

IF 56.1 1区医学

Cancer Cell Pub Date : 2026-07-13 Epub Date: 2026-05-07 DOI: 10.1016/j.ccell.2026.04.005

Courtney T S Kureshi, Michael J Walsh, Rakeeb Kureshi, Victoire Cardot-Ruffino, Dennis A Agardy, Lestat R Ali, James M Dougan, Li Qiang, Jiao Shen, Chong Zuo, Patrick J Lenehan, S Jennifer Wang, Eugena Chang, Joshua Remland, Lauren Brais, Thomas E Clancy, James M Cleary, Jason L Hornick, Brandon M Huffman, Joseph D Mancias, George Molina, Mark Fairweather, Jonathan A Nowak, Kimberly J Perez, Douglas A Rubinson, Sarah Slater, Ritchell van Dams, Jiping Wang, Brian M Wolpin, Lei Zhao, Katharine Barrientos, Ruslan Novosiadly, Miranda Broz, Harshabad Singh, Michael Dougan, Stephanie K Dougan

{"title":"Dendritic cell redundancy enables priming of anti-tumor CD4+ T cells in pancreatic cancer.","authors":"Courtney T S Kureshi, Michael J Walsh, Rakeeb Kureshi, Victoire Cardot-Ruffino, Dennis A Agardy, Lestat R Ali, James M Dougan, Li Qiang, Jiao Shen, Chong Zuo, Patrick J Lenehan, S Jennifer Wang, Eugena Chang, Joshua Remland, Lauren Brais, Thomas E Clancy, James M Cleary, Jason L Hornick, Brandon M Huffman, Joseph D Mancias, George Molina, Mark Fairweather, Jonathan A Nowak, Kimberly J Perez, Douglas A Rubinson, Sarah Slater, Ritchell van Dams, Jiping Wang, Brian M Wolpin, Lei Zhao, Katharine Barrientos, Ruslan Novosiadly, Miranda Broz, Harshabad Singh, Michael Dougan, Stephanie K Dougan","doi":"10.1016/j.ccell.2026.04.005","DOIUrl":"10.1016/j.ccell.2026.04.005","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is resistant to current immunotherapies and lacks effective anti-tumor CD8+ T cells, which is potentially due to insufficient cross-presentation by cDC1s. Here, we combine a STING agonist with anti-CTLA-4 and anti-PD-1 to achieve durable remissions and immunologic memory in multiple mouse models of poorly immunogenic PDAC. We find that tumor control does not depend on CD8+ T cells or tumor cell MHC expression but instead requires IFNγ-producing CD4+ T cells (Th1s) that are primed by dendritic cells in lymph nodes. The triple combination immunotherapy induces an accumulation of activated cDC2s carrying tumor antigen into tumor-draining lymph nodes; cDC2s are required for orthotopic tumor clearance. Intratumoral CD4+ T cells and cDC2s remain present in treatment-naive and chemotherapy-exposed human PDAC. In chemotherapy-exposed patients' blood, cDC2s outnumber cDC1s by 10-fold. Therefore, therapeutic targeting of the cDC2-CD4+ T cell-IFNγ axis could be efficacious in PDAC.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1381-1400.e9"},"PeriodicalIF":56.1,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13430408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855946","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}

引用次数: 0

The cartography of KRAS inhibitor resistance in colorectal cancer. 结直肠癌中KRAS抑制剂的耐药图谱。

IF 56.1 1区医学

Cancer Cell Pub Date : 2026-07-13 Epub Date: 2026-06-11 DOI: 10.1016/j.ccell.2026.05.010

Mark White, Andrew D Campbell, Owen J Sansom

引用次数: 0

Concurrent genetic and non-genetic resistance mechanisms to KRAS inhibition in colorectal cancer. 结直肠癌中KRAS抑制的同步遗传和非遗传耐药机制。

IF 56.1 1区医学

Cancer Cell Pub Date : 2026-07-13 Epub Date: 2026-05-21 DOI: 10.1016/j.ccell.2026.04.009

Salvador Alonso, Kevan Chu, Elizabeth Granowsky, Valeria Saraiba Rabanales, Marie J Parsons, Himari Gunasinghe, Jinru Shia, Rona Yaeger, Lukas E Dow

{"title":"Concurrent genetic and non-genetic resistance mechanisms to KRAS inhibition in colorectal cancer.","authors":"Salvador Alonso, Kevan Chu, Elizabeth Granowsky, Valeria Saraiba Rabanales, Marie J Parsons, Himari Gunasinghe, Jinru Shia, Rona Yaeger, Lukas E Dow","doi":"10.1016/j.ccell.2026.04.009","DOIUrl":"10.1016/j.ccell.2026.04.009","url":null,"abstract":"KRAS is mutationally activated in 45%-50% of colorectal cancer (CRC) cases, and while KRAS-targeted therapies have shown clinical promise, drug resistance limits their efficacy. To explore the mechanisms underlying KRAS inhibitor resistance, we use targeted exome sequencing and spatial transcriptomics on patient-matched CRC biopsies following combined treatment with KRASG12C and EGFR inhibitors. We show that acquired genetic events are identified in most patients at progression but are often subclonal and coexist with transcriptional adaptive states. Mesenchymal, YAP, and fetal-like transcriptional signatures predominate in resistant tumors, while inflammatory programs are induced early on treatment. Single-cell spatial analysis reveals intratumoral heterogeneity, with diverse adaptive states in different zones of individual tumors. Using human and murine organoid models, we show that drug-induced inflammatory programs are, at least in part, cancer-cell autonomous, and precede the emergence of drug resistance. We identify TBK1 as a target to abrogate the inflammatory adaptive phase and enhance responses to KRAS inhibition.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1368-1380.e8"},"PeriodicalIF":56.1,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13417870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986587","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}

引用次数: 0

An epigenetic four-lane route to camouflage for cancer cells. 一种伪装癌细胞的表观遗传四车道路线。

IF 56.1 1区医学

Cancer Cell Pub Date : 2026-07-13 Epub Date: 2026-06-11 DOI: 10.1016/j.ccell.2026.05.017

Lorenzo Galluzzi, Gwenola Manic, Ilio Vitale

引用次数: 0

Hypoxia shapes both therapeutic response and resistance in metastatic clear cell renal cell carcinoma. 缺氧影响转移性透明细胞肾细胞癌的治疗反应和耐药性。

IF 56.1 1区医学

Cancer Cell Pub Date : 2026-07-13 Epub Date: 2026-06-04 DOI: 10.1016/j.ccell.2026.05.007

Lynda Vuong, Andrew E Cornish, Jennifer Pfeil, Yash Khandwala, Hui Jiang, Doris X T Zheng, Eduardo A Mascareno, Nicole Rittenhouse, Phillip M Rappold, Josef Leibold, Erich A Sabio, Kate Weiss, Carlene Gonzalez, Liangliang Ji, Jing Zhang, Mojca Adlesic, Oguz Akin, Jessica Flynn, Chirag Krishna, Andrea Lopez Sanmiguel, Rebecca A Sager, Tiak J Tan, Alejandro Sanchez, Renzo G Di Natale, Kyle A Blum, Paul Russo, Jonathan A Coleman, Ian J Frew, Diego Chowell, Ying-Bei Chen, David B Solit, Irina Ostrovnaya, Robert J Motzer, Martin H Voss, Ritesh R Kotecha, Timothy A Chan, Hartland W Jackson, Fengshen Kuo, Ming O Li, A Ari Hakimi

{"title":"Hypoxia shapes both therapeutic response and resistance in metastatic clear cell renal cell carcinoma.","authors":"Lynda Vuong, Andrew E Cornish, Jennifer Pfeil, Yash Khandwala, Hui Jiang, Doris X T Zheng, Eduardo A Mascareno, Nicole Rittenhouse, Phillip M Rappold, Josef Leibold, Erich A Sabio, Kate Weiss, Carlene Gonzalez, Liangliang Ji, Jing Zhang, Mojca Adlesic, Oguz Akin, Jessica Flynn, Chirag Krishna, Andrea Lopez Sanmiguel, Rebecca A Sager, Tiak J Tan, Alejandro Sanchez, Renzo G Di Natale, Kyle A Blum, Paul Russo, Jonathan A Coleman, Ian J Frew, Diego Chowell, Ying-Bei Chen, David B Solit, Irina Ostrovnaya, Robert J Motzer, Martin H Voss, Ritesh R Kotecha, Timothy A Chan, Hartland W Jackson, Fengshen Kuo, Ming O Li, A Ari Hakimi","doi":"10.1016/j.ccell.2026.05.007","DOIUrl":"10.1016/j.ccell.2026.05.007","url":null,"abstract":"Vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors (VEGFR-TKIs) and anti-PD-1 (aPD-1) combinations are effective in multiple solid tumors, particularly in clear cell renal cell carcinoma (ccRCC), due to its characteristic pseudohypoxic, hyper-angiogenic state driven by biallelic VHL loss. However, long-term durability is inferior to dual aPD-1/anti-CTLA-4 regimens, yet the underlying mechanisms remain unclear. We investigated tumor microenvironment evolution following VEGFR-TKI, aPD-1, and combined VEGFR-TKI/aPD-1 treatment in a transgenic ccRCC mouse model. We identify hypoxia-responsive SPP1+ tumor-associated macrophages (TAMs) that infrequently infiltrate baseline pseudohypoxic tumors. This proxy of true hypoxia tracks with successful response to VEGFR-TKI/aPD-1 in mouse and human on-treatment single-cell RNA sequencing and imaging mass cytometry cohorts, reflecting treatment-induced hypoxic necrosis. Paradoxically, pretreatment hypoxia predicted worse outcomes across VEGFR-TKI/aPD-1 trials and real-world cohorts while extended exposure to hypoxia-inducing VEGFR-TKIs exacerbated metastasis in mice, highlighting the dual implications of hypoxia in ccRCC disease trajectory.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1477-1495.e15"},"PeriodicalIF":56.1,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13383571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161978","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}

引用次数: 0

Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts. 分子表型和空间原型：癌症相关成纤维细胞的新框架。

IF 56.1 1区医学

Cancer Cell Pub Date : 2026-07-13 Epub Date: 2026-06-25 DOI: 10.1016/j.ccell.2026.06.001

Yunhe Liu, Xiongfeng Chen, Yibo Dai, Yiyue Jia, Yann Kieffer, Luyu Xie, Zhuan Zhou, Lauren Tyler, Alex C Kim, Giulia Biffi, Akshay T Krishnamurty, Fatima Mechta-Grigoriou, Ruth Scherz-Shouval, Mara H Sherman, Shannon J Turley, Linghua Wang, Huocong Huang

{"title":"Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts.","authors":"Yunhe Liu, Xiongfeng Chen, Yibo Dai, Yiyue Jia, Yann Kieffer, Luyu Xie, Zhuan Zhou, Lauren Tyler, Alex C Kim, Giulia Biffi, Akshay T Krishnamurty, Fatima Mechta-Grigoriou, Ruth Scherz-Shouval, Mara H Sherman, Shannon J Turley, Linghua Wang, Huocong Huang","doi":"10.1016/j.ccell.2026.06.001","DOIUrl":"10.1016/j.ccell.2026.06.001","url":null,"abstract":"Cancer-associated fibroblasts (CAFs) form a dynamic ecosystem that critically influences tumor progression and therapeutic response. Although recent advances in single-cell and spatial omics have uncovered profound stromal diversity, interpreting the mechanistic relevance of this complexity remains a challenge. Here, we propose a more unifying conceptual framework to bridge high-dimensional data with experimental biology. By categorizing CAFs into conserved molecular phenotypes and distinct spatial archetypes, this model illustrates how CAF identities are intimately linked to local tissue contexts. This refined framework brings the complexity of the tumor stroma into greater focus, underscoring the necessary transition from broad stromal targeting toward precision, context-specific modulation. Ultimately, we hope this integrated effort will aid in the collaborative development of next-generation therapies that selectively target pathogenic stroma in cancer to improve patient outcomes.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1346-1367"},"PeriodicalIF":56.1,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13383123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148327139","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}

引用次数: 0

Targeting tumor-intrinsic STK40 induces immune vulnerability and drives T cell reinvigoration. 靶向肿瘤固有的STK40诱导免疫脆弱性并驱动T细胞再生。

IF 56.1 1区医学

Cancer Cell Pub Date : 2026-07-13 Epub Date: 2026-05-28 DOI: 10.1016/j.ccell.2026.05.001

Lili Zhu, Sisi Zhang, Botai Li, Xueliang Liu, Chen Yang, Xiangyu Tang, Jiayi Chai, Xupeng Yang, Chune Yu, Huiping Liao, Zhirui Cao, Long Liao, Wei Wang, Shengxian Yuan, Qiang Gao, Chong Sun, René Bernards, Yu Yang, Wenxin Qin, Cun Wang

{"title":"Targeting tumor-intrinsic STK40 induces immune vulnerability and drives T cell reinvigoration.","authors":"Lili Zhu, Sisi Zhang, Botai Li, Xueliang Liu, Chen Yang, Xiangyu Tang, Jiayi Chai, Xupeng Yang, Chune Yu, Huiping Liao, Zhirui Cao, Long Liao, Wei Wang, Shengxian Yuan, Qiang Gao, Chong Sun, René Bernards, Yu Yang, Wenxin Qin, Cun Wang","doi":"10.1016/j.ccell.2026.05.001","DOIUrl":"10.1016/j.ccell.2026.05.001","url":null,"abstract":"Immunotherapy has revolutionized cancer treatment, yet its efficacy in hepatocellular carcinoma (HCC) remains limited and the mechanisms of resistance are poorly defined. Using in vivo CRISPR-Cas9 screens, we identify serine/threonine kinase 40 (STK40) as a previously unrecognized regulator of immune evasion. Stk40 ablation synergizes with PD-1 blockade to induce tumor regression. Hepatocyte-specific Stk40 deletion abolishes tumorigenesis in hydrodynamic plasmid-driven HCC models. Mechanistically, STK40 scaffolds the COP1 ubiquitin ligase to promote interferon gamma receptor 1 (IFNGR1) degradation. Genetic depletion of Stk40 stabilizes IFNGR1, restoring tumor cell sensitivity to T cell cytotoxicity. Concurrently, Stk40 loss triggers autonomous GM-CSF secretion, enhancing the infiltration and activation of conventional type 1 dendritic cells, which promotes antigen cross-presentation and CD8+ T cell activation. Pharmacological inhibition of STK40 using LNP-siRNA, combined with PD-1 blockade, elicits potent anti-tumor responses across multiple cancer types. These findings establish STK40 as a dual-action therapeutic target to overcome resistance to anti-tumor immunity.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1496-1508.e10"},"PeriodicalIF":56.1,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052988","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}

引用次数: 0

Clonal lineage tracing of innate immune cells in human cancer. 人类肿瘤中先天免疫细胞的克隆谱系追踪。

IF 56.1 1区医学

Cancer Cell Pub Date : 2026-07-13 Epub Date: 2026-06-04 DOI: 10.1016/j.ccell.2026.05.006

Vincent Liu, Katalin Sandor, Patrick K Yan, Zhuang Miao, Yajie Yin, Robert R Stickels, Andy Y Chen, Kamir Hiam-Galvez, Jacob Gutierrez, Wenxi Zhang, Sairaj M Sajjath, Raeline Valbuena, Steven Wang, Bence Daniel, Leif S Ludwig, Brooke E Howitt, Caleb A Lareau, Ansuman T Satpathy

{"title":"Clonal lineage tracing of innate immune cells in human cancer.","authors":"Vincent Liu, Katalin Sandor, Patrick K Yan, Zhuang Miao, Yajie Yin, Robert R Stickels, Andy Y Chen, Kamir Hiam-Galvez, Jacob Gutierrez, Wenxi Zhang, Sairaj M Sajjath, Raeline Valbuena, Steven Wang, Bence Daniel, Leif S Ludwig, Brooke E Howitt, Caleb A Lareau, Ansuman T Satpathy","doi":"10.1016/j.ccell.2026.05.006","DOIUrl":"10.1016/j.ccell.2026.05.006","url":null,"abstract":"Innate immune cells constitute the majority of the tumor microenvironment (TME) and mediate anti-tumor immunity and immunotherapy responses. While single-cell T and B cell receptor sequencing have revealed insights into the clonal dynamics of adaptive immunity, the lack of analogous tools has precluded similar analysis of innate immune cells. Here, we describe a method leveraging somatic mitochondrial DNA (mtDNA) mutations to reconstruct clonal lineage relationships between cells in native human tissues. By jointly profiling single-cell chromatin accessibility and mtDNA variants, we resolve clonal dynamics of 218,715 cells from matched tumors, tissues, and blood from patients with lung and ovarian cancers. Clonal tracing reveals that TME-resident myeloid subsets, including macrophages and type 3 dendritic cells (DC3), are clonally related to circulating and tissue-infiltrating monocytes. We further identify distinct DC-biased and macrophage-biased clones, whose circulating monocyte precursors exhibit distinct epigenetic profiles, suggesting intratumoral myeloid differentiation fate may be peripherally programmed before TME infiltration.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":" ","pages":"1509-1521.e4"},"PeriodicalIF":56.1,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13309241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161958","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}

引用次数: 0

Attack of the clones: Tracing the dynamics of innate immune cells in human cancer. 克隆的攻击：在人类癌症中追踪先天免疫细胞的动态。

IF 56.1 1区医学

Cancer Cell Pub Date : 2026-07-13 Epub Date: 2026-06-11 DOI: 10.1016/j.ccell.2026.05.013

Amir Brivanlou, Nir Hacohen

引用次数: 0

Extracellular vesicles: Whisperers of tumor immune evasion. 细胞外囊泡：肿瘤免疫逃避的低语者。

IF 44.5 1区医学

Cancer Cell Pub Date : 2026-06-08 Epub Date: 2026-05-07 DOI: 10.1016/j.ccell.2026.03.010

An Hendrix, Olivier De Wever

引用次数: 0