Cancer Cell最新文献

英文中文

When blood mutations turn beneficial 当血液突变变得有益时

IF 50.3 1区医学 Q1 CELL BIOLOGY

Cancer Cell

Pub Date : 2025-12-04 DOI: 10.1016/j.ccell.2025.11.004

Carlos de la Calle-Fabregat, Elsa Bernard, Florent Ginhoux

Clonal hematopoiesis (CH), an expansion of hematopoietic clones harboring somatic mutations, is common in patients with solid tumors and associates with poor outcomes. In this issue of Cancer Cell, a study shows that, in response to immunotherapy, TET2-mutant CH enhances macrophage antigen presentation and CD8⁺ T cell activation, thereby improving therapeutic efficacy.

克隆造血（CH）是一种包含体细胞突变的造血克隆的扩展，在实体瘤患者中很常见，并与不良预后相关。在这一期的Cancer Cell上，一项研究表明，tet2突变体CH在免疫治疗的反应中增强了巨噬细胞抗原呈递和CD8 + T细胞活化，从而提高了治疗效果。

引用次数: 0

Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche 肿瘤启动干细胞微调中性粒细胞的可塑性，以塑造一个保护生态位

IF 50.3 1区医学 Q1 CELL BIOLOGY

Cancer Cell

Pub Date : 2025-12-04 DOI: 10.1016/j.ccell.2025.11.001

Weijie Guo, Jingyun Luan, Xuejie Huang, Daniel Leon, Sophie Gang, Benjamin Nicholson, Breanna Bertacchi, Diana Bolotin, Mark W. Lingen, Alexander T. Pearson, Evgeny Izumchenko, Ari J. Rosenberg, Nishant Agrawal, Everett E. Vokes, Siwakorn Punyawatthananukool, Shuh Narumiya, Matthias Gunzer, Iván Ballesteros, Andrés Hidalgo, Yuxuan Miao

The heterogeneous nature of tumor-associated neutrophils (TANs) has been recognized, but how different cell states of TANs emerge, evolve, distribute, and impact cancer immunotherapy efficacy remain elusive. Using single-cell RNA sequencing, spatial transcriptomics, and genetic manipulations, we show that anti-PDL1 + CD40 agonist immunotherapy can induce interferon responses in TANs, allowing them to regain anti-tumor activities in squamous cell carcinomas (SCCs). In contrast, TANs residing at the tumor-stroma interface can preserve their immune-suppressive state. Importantly, we identify a group of SOX2^High tumor-initiating stem cells (tSCs) at the tumor-stroma interface that upregulate fatty acid desaturase 1 (Fads1) to produce arachidonic acid (AA). This tSC-specific pathway enhances the prostaglandin E₂ (PGE₂) signaling in TANs, which can disrupt the interferon response and prevent the interferon-induced anti-tumor functions in TANs. By fine-tuning the plasticity of neutrophils, tSCs shape neutrophil heterogeneity and sculpt a protective micro-niche to survive from immunotherapy and drive cancer relapse.

肿瘤相关中性粒细胞（TANs）的异质性已经被认识到，但TANs的不同细胞状态如何出现、进化、分布和影响癌症免疫治疗效果仍然是一个谜。通过单细胞RNA测序、空间转录组学和基因操作，我们发现抗pdl1 + CD40激动剂免疫治疗可以诱导TANs中的干扰素反应，使其在鳞状细胞癌（SCCs）中恢复抗肿瘤活性。相反，在肿瘤-基质界面的TANs可以保持其免疫抑制状态。重要的是，我们在肿瘤-基质界面发现了一组SOX2High tumor- initiation stem cells (tSCs)，它们上调脂肪酸去饱和酶1 （Fads1）以产生花生四烯酸（AA）。这种tsc特异性通路增强了TANs中的前列腺素E2 （PGE2）信号，从而破坏干扰素应答并阻止干扰素诱导的TANs抗肿瘤功能。通过微调中性粒细胞的可塑性，tsc塑造了中性粒细胞的异质性，塑造了一个保护性的微生态位，从而在免疫治疗中存活下来，并驱动癌症复发。

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引用次数: 0

Advancing CNS tumor diagnostics with expanded DNA methylation-based classification 扩展DNA甲基化分类推进中枢神经系统肿瘤诊断

IF 50.3 1区医学 Q1 CELL BIOLOGY

Cancer Cell

Pub Date : 2025-12-04 DOI: 10.1016/j.ccell.2025.11.002

Martin Sill, Daniel Schrimpf, Areeba Patel, Dominik Sturm, Natalie Jäger, Philipp Sievers, Leonille Schweizer, Rouzbeh Banan, David Reuss, Abigail Suwala, Andrey Korshunov, Damian Stichel, Annika K. Wefers, Ann-Christin Hau, Henning Boldt, Patrick N. Harter, Zied Abdullaev, Jamal Benhamida, Daniel Teichmann, Arend Koch, Felix Sahm

DNA methylation-based classification is now central to contemporary neuro-oncology, as highlighted by the World Health Organization (WHO) classification of central nervous system (CNS) tumors. We present the Heidelberg CNS Tumor Methylation Classifier version 12.8 (v12.8), trained on 7,495 methylation profiles, which expands recognized entities from 91 classes in version 11 (v11) to 184 subclasses. This expansion is a result of newly identified tumor types discovered through our large online repository and global collaborations, underscoring CNS tumor heterogeneity. The random forest-based classifier achieves 95% subclass-level accuracy, with its well-calibrated probabilistic scores providing a reliable measure of confidence for each classification. Its hierarchical output structure enables interpretation across subclass, class, family, and superfamily levels, thereby supporting clinical decisions at multiple granularities. Comparative analyses demonstrate that v12.8 surpasses previous versions and conventional WHO-based approaches. These advances highlight the improved precision and practical utility of the updated classifier in personalized neuro-oncology.

基于DNA甲基化的分类现在是当代神经肿瘤学的核心，正如世界卫生组织（WHO）中枢神经系统（CNS）肿瘤的分类所强调的那样。我们提出了Heidelberg CNS肿瘤甲基化分类器版本12.8 (v12.8)，对7,495个甲基化谱进行了训练，将版本11 （v11）中的91类识别实体扩展到184个子类。这种扩展是通过我们的大型在线存储库和全球合作发现的新发现的肿瘤类型的结果，强调了中枢神经系统肿瘤的异质性。基于随机森林的分类器达到95%的子类水平精度，其校准良好的概率分数为每个分类提供了可靠的置信度度量。它的分层输出结构支持跨子类、类、家族和超家族级别的解释，从而支持多粒度的临床决策。对比分析表明，v12.8版本超越了以前的版本和传统的基于世卫组织的方法。这些进步突出了个性化神经肿瘤学中更新分类器的精度和实用性的提高。

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引用次数: 0

Spatial patterns of glioblastoma 胶质母细胞瘤的空间格局

IF 50.3 1区医学 Q1 CELL BIOLOGY

Cancer Cell

Pub Date : 2025-11-20 DOI: 10.1016/j.ccell.2025.10.013

Toshiro Hara, Cong Ma

Glioblastoma features extensive gene expression heterogeneity and high lethality, yet the mechanisms underlying this heterogeneity and its link to clinical outcomes remain elusive. In this issue of Cancer Cell, Migliozzi et al. spatially profile glioblastoma specimens to uncover cellular mechanisms that govern the extent of the heterogeneity in malignant cells.

胶质母细胞瘤具有广泛的基因表达异质性和高致死率，但这种异质性的机制及其与临床结果的联系尚不清楚。在这一期的《癌细胞》杂志上，Migliozzi等人对胶质母细胞瘤标本进行了空间分析，以揭示恶性细胞异质性程度的细胞机制。

引用次数: 0

MED1-driven ecDNA super-enhancers in cancer 癌症中med1驱动的ecDNA超增强子

IF 50.3 1区医学 Q1 CELL BIOLOGY

Cancer Cell

Pub Date : 2025-11-13 DOI: 10.1016/j.ccell.2025.10.011

Jiaqi Zhou, Xing Kang, Yang Zhang, Haiyun Gan

Extrachromosomal circular DNA (ecDNA), enriched with enhancers, drives oncogenic transcription and tumor progression, but the mechanisms remain elusive. In this issue of Cancer Cell, Wei et al. uncover MED1-driven ecDNA super-enhancers as regulatory hubs and show that disrupting ecDNA-containing condensates selectively impairs transcription and induces apoptosis in a cancer-type-specific manner.

染色体外环状DNA （ecDNA）富含增强子，可驱动致癌转录和肿瘤进展，但其机制尚不明确。在这一期的《Cancer Cell》中，Wei等人揭示了med1驱动的ecDNA超增强子作为调控枢纽，并表明破坏含有ecDNA的凝聚物选择性地损害转录并以癌症类型特异性的方式诱导细胞凋亡。

引用次数: 0

Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer paneth样转化驱动结直肠癌中KRAS和EGFR双靶向的耐药性

IF 50.3 1区医学 Q1 CELL BIOLOGY

Cancer Cell

Pub Date : 2025-11-13 DOI: 10.1016/j.ccell.2025.10.010

Yuetong Zhang, Jiaying Chen, Yong She, Zhaoyuan Fang, Yaxin Zhang, Danyun Ruan, Wenjun Guo, Jianping Liao, Weiping Zhou, Jianpei Lao, Weicheng Fang, Xingyan Pan, Wenfei Kang, Zifeng Wang, Yuanzhong Wu, Rong Deng, Lin Tian, Liqin Wang, Huilin Huang, Jian Zheng, Yijun Gao

While dual KRAS and epidermal growth factor receptor (EGFR) inhibition shows promise in treating KRAS-mutant colorectal cancer (CRC), resistance remains a major challenge. Using genetically engineered mouse models, patient-derived organoids and xenografts, as well as clinical specimens, we discover that colorectal tumors surviving combined KRAS and EGFR inhibition acquire a Paneth-like cell state—a secretory lineage typically confined to the intestinal crypt. Lineage tracing reveals that CRC cells evade dual therapy by transitioning into a Paneth-like state. Through integrated transcriptomic analysis and CRISPR genetic screening, we identify SMAD1 as a key regulator of this lineage plasticity, promoting resistance by directly activating FGFR3. Genetic or pharmacological inhibition of FGFR3 prevents the Paneth-like transition, restores drug sensitivity, and synergizes with KRAS-EGFR inhibition across multiple preclinical models. These findings reveal that the SMAD1-FGFR3 axis triggers Paneth-like plasticity to drive KRAS-EGFR dual therapy resistance in CRC and highlight FGFR3 blockade as a promising strategy to overcome plasticity-driven drug tolerance.

虽然双重KRAS和表皮生长因子受体（EGFR）抑制在治疗KRAS突变型结直肠癌（CRC）中显示出希望，但耐药性仍然是主要挑战。通过基因工程小鼠模型、患者来源的类器官和异种移植物以及临床标本，我们发现KRAS和EGFR联合抑制后存活的结直肠肿瘤获得了paneth样细胞状态——一种通常局限于肠隐窝的分泌谱系。谱系追踪显示CRC细胞通过转变为paneth样状态来逃避双重治疗。通过整合转录组学分析和CRISPR基因筛选，我们确定SMAD1是该谱系可塑性的关键调节因子，通过直接激活FGFR3来促进抗性。FGFR3的遗传或药理学抑制可阻止paneth样转变，恢复药物敏感性，并在多个临床前模型中与KRAS-EGFR抑制协同作用。这些研究结果表明，SMAD1-FGFR3轴触发panethlike可塑性以驱动CRC中KRAS-EGFR双药耐药，并强调FGFR3阻断是克服可塑性驱动的药物耐受性的有希望的策略。

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引用次数: 0

Exercising through cancer: Physical activity as medicine for cancer care 通过癌症锻炼：体育活动作为癌症治疗的药物

IF 50.3 1区医学 Q1 CELL BIOLOGY

Cancer Cell

Pub Date : 2025-11-13 DOI: 10.1016/j.ccell.2025.10.009

David M. Nash, Lauren V. Terry, Mark A. Febbraio

Exercise holds significant potential as an adjunct therapy in cancer, extending beyond quality-of-life improvements to influencing tumor progression, treatment response, and survival. Its clinical integration remains limited by variability in models, heterogenous interventions, and the absence of predictive biomarkers. As the field progresses, identifying molecular effectors of exercise, in addition to emphasizing practical clinical translation, is essential. This commentary highlights the anti-tumor effects of exercise and evaluates how exercise can advance from supportive care to a targeted, evidence-based component of cancer treatment.

运动作为癌症的辅助疗法具有巨大的潜力，不仅可以改善生活质量，还可以影响肿瘤进展、治疗反应和生存。其临床整合仍然受到模型可变性、异质性干预和缺乏预测性生物标志物的限制。随着该领域的发展，除了强调实际的临床转化外，识别运动的分子效应也是必不可少的。这篇评论强调了运动的抗肿瘤作用，并评估了运动如何从支持性护理发展到有针对性的、基于证据的癌症治疗组成部分。

引用次数: 0

Long-range cholinergic input promotes glioblastoma progression. 远距离胆碱能输入促进胶质母细胞瘤的进展。

IF 44.5 1区医学 Q1 CELL BIOLOGY

Cancer Cell

Pub Date : 2025-11-10 Epub Date: 2025-08-18 DOI: 10.1016/j.ccell.2025.07.024

Yang Yang, Chuanyan Yang, Xuezhu Chen, Yibin Jiang, Xuejiao Lei, Kang Ma, Yulian Quan, Tianran Li, Chenfu Guo, Yijing Meng, Lin Kang, Xinyu Zhang, Long Jin, Jiafeng Huang, Ning Mu, Zexuan Yan, Qinghua Ma, Shuai Wang, Yanxia Wang, Yong-Ning Shang, Cong Chen, Yu Shi, Shukun Hu, Likun Yang, Chuan Lan, Rong Hu, Ying Zhang, Xia Li, Yunqing Li, Chong Liu, Yu-Hai Wang, Fei Li, Hua Feng, Xiu-Wu Bian, Tunan Chen

Glioblastoma (GBM), the most aggressive primary brain tumor, is shaped by its integration into neural networks. While glutamatergic input is linked to tumor progression, the broader architecture and function of neuron-glioma connectomes remain unclear. Using monosynaptic rabies tracing, we map brain-wide neural input to patient-derived xenografts and reveal a consistent organizational logic: local inputs are primarily glutamatergic, while long-range connections exhibit diverse neurotransmitter profiles, with basal forebrain cholinergic projections emerging as a conserved input across sites. Functionally, presynaptic acetylcholine release promotes GBM progression through muscarinic receptor CHRM3 in a circuit-specific manner. Mechanistically, glutamatergic and cholinergic signals converge to enhance glioma calcium transients but diverge in temporal transcriptional control, with their dual blockade producing additive anti-tumor effects. Therapeutically, the anticholinergic drug scopolamine attenuates glioma growth, whereas the acetylcholinesterase inhibitor donepezil exacerbates disease. These findings reveal the complexity of neuron-glioma connectivity, highlighting long-range neuromodulatory pathways as promising therapeutic targets in GBM.

胶质母细胞瘤（GBM）是最具侵袭性的原发性脑肿瘤，其形成与神经网络的整合。虽然谷氨酸能输入与肿瘤进展有关，但神经胶质瘤连接体的更广泛的结构和功能尚不清楚。通过单突触狂犬病追踪，我们将全脑神经输入映射到患者来源的异种移植物，并揭示了一致的组织逻辑：局部输入主要是谷氨酸，而远程连接表现出不同的神经递质谱，基底前脑胆碱能投射作为跨部位的保守输入出现。功能上，突触前乙酰胆碱释放通过毒蕈碱受体CHRM3以电路特异性方式促进GBM进展。从机制上讲，谷氨酸能和胆碱能信号聚集在一起增强胶质瘤钙瞬态，但在时间转录控制上存在分歧，它们的双重阻断产生叠加的抗肿瘤作用。在治疗上，抗胆碱能药物东莨菪碱能减缓胶质瘤的生长，而乙酰胆碱酯酶抑制剂多奈哌齐则会加重疾病。这些发现揭示了神经元-胶质瘤连接的复杂性，强调了远距离神经调节通路是GBM有希望的治疗靶点。

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引用次数: 0

Engineered natural killer cells for cancer therapy. 用于癌症治疗的工程自然杀伤细胞。

IF 44.5 1区医学 Q1 CELL BIOLOGY

Cancer Cell

Pub Date : 2025-11-10 Epub Date: 2025-10-23 DOI: 10.1016/j.ccell.2025.09.013

Alexander Biederstädt, Katayoun Rezvani

Allogeneic natural killer (NK) cell immunotherapy is emerging as a promising and scalable, off-the-shelf platform for treating relapsed and refractory cancers. Early-phase clinical trials have demonstrated remarkable safety and encouraging therapeutic efficacy of chimeric antigen receptor (CAR)-NK cells in heavily pretreated patients with lymphoid malignancies. Current efforts are expanding these therapies to solid tumors, with translational research increasingly leveraging precision gene editing to enhance effector function, persistence, and resistance to the immunosuppressive tumor microenvironment. In this review, we summarize findings from early-phase clinical trials and discuss emerging synthetic biology and engineering approaches to improve NK cell potency. We also highlight advances in high-throughput discovery platforms that have identified actionable gene targets for NK cell reprogramming, offering a path to design multi-engineered CAR-NK cells to overcome the challenges of solid tumors. Together, these translational innovations define the trajectory of next-generation NK cell therapies and their integration into the broader cancer immunotherapy landscape.

同种异体自然杀伤（NK）细胞免疫疗法正在成为治疗复发和难治性癌症的一种有前途的、可扩展的现成平台。早期临床试验已经证明嵌合抗原受体(CAR)-NK细胞在淋巴细胞恶性肿瘤患者中具有显著的安全性和令人鼓舞的治疗效果。目前的努力正在将这些疗法扩展到实体肿瘤，转化研究越来越多地利用精确的基因编辑来增强效应物的功能、持久性和对免疫抑制肿瘤微环境的抵抗力。在这篇综述中，我们总结了早期临床试验的发现，并讨论了新兴的合成生物学和工程方法来提高NK细胞的效力。我们还强调了高通量发现平台的进展，这些平台已经确定了NK细胞重编程的可操作基因靶点，为设计多工程CAR-NK细胞以克服实体肿瘤的挑战提供了一条途径。总之，这些转化创新定义了下一代NK细胞疗法的发展轨迹，并将其整合到更广泛的癌症免疫治疗领域。

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引用次数: 0

The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression. 多梳抑制复合体1通过协调干细胞和免疫抑制驱动双阴性前列腺癌转移。

IF 44.5 1区医学 Q1 CELL BIOLOGY

Cancer Cell

Pub Date : 2025-11-10 Epub Date: 2025-10-24 DOI: 10.1016/j.ccell.2025.10.005

Wenjing Su, Hyun Ho Han, Yan Wang, Boyu Zhang, Bing Zhou, Yuanming Cheng, Alekya Rumandla, Sreeharsha Gurrapu, Goutam Chakraborty, Jie Su, Guangli Yang, Xin Liang, Guocan Wang, Neal Rosen, Howard I Scher, Ouathek Ouerfelli, Filippo G Giancotti

引用次数: 0

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