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Epitranscriptomic control of cancer hallmarks: Functions, mechanisms, and therapeutics of RNA modifications 癌症特征的表转录组学控制:RNA修饰的功能、机制和治疗方法
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2025-12-24 DOI: 10.1016/j.ccell.2025.12.001
Xiaolan Deng, Dong Wu, Yingqi Zhao, Ying Qing, Huizhe Wu, Jianjun Chen
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引用次数: 0
Targeting STING to generate therapeutic anti-tumor immunity 靶向STING产生治疗性抗肿瘤免疫
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2025-12-24 DOI: 10.1016/j.ccell.2025.12.002
Caroline G. Fahey, Anthony F. Cordova, Patrick C. Gedeon, David A. Barbie
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway bridges cytosolic DNA sensing with type I interferon activation in cancer. Despite promising preclinical results, generating clinically meaningful anti-tumor immunity with STING agonists has faced substantial challenges, highlighting gaps in model systems and the biologic complexity of STING signaling. In the tumor microenvironment (TME), STING activation elicits highly context- and cell type-dependent outcomes, with divergent effects on tumor cells, myeloid cells, T cells, and other cell types. Furthermore, the downstream induction of type I interferon and other cytokines in the TME can have both pro- and anti-tumorigenic consequences, with emerging interferon-independent functions of STING signaling adding further complexity. In this review, we chart the diverse impact of STING activation across the TME and discuss how recent insights can inform the design of next-generation therapeutic strategies that more effectively harness STING-driven innate immunity to promote durable anti-tumor activity in humans.
环状GMP-AMP合成酶(cGAS)-干扰素基因刺激因子(STING)通路在肿瘤细胞胞质DNA传感与I型干扰素激活之间架起了桥梁。尽管有很好的临床前结果,但利用STING激动剂产生具有临床意义的抗肿瘤免疫仍然面临着巨大的挑战,这突出了模型系统的差距和STING信号传导的生物学复杂性。在肿瘤微环境(TME)中,STING激活引发高度依赖环境和细胞类型的结果,对肿瘤细胞、骨髓细胞、T细胞和其他细胞类型具有不同的影响。此外,I型干扰素和其他细胞因子在TME中的下游诱导可能具有促肿瘤和抗肿瘤的作用,STING信号的干扰素独立功能的出现进一步增加了复杂性。在这篇综述中,我们绘制了整个TME中STING激活的不同影响,并讨论了最近的见解如何为下一代治疗策略的设计提供信息,这些策略可以更有效地利用STING驱动的先天免疫来促进人类持久的抗肿瘤活性。
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引用次数: 0
Circulating tumor DNA as a biomarker in early phase clinical trials 循环肿瘤DNA作为早期临床试验的生物标志物
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2025-12-19 DOI: 10.1016/j.ccell.2025.11.011
Harold N. Tan, Mitchell J. Elliott, Ian M. Silverman, Lillian L. Siu, Timothy A. Yap
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引用次数: 0
Multi-omic landscape of human gliomas from diagnosis to treatment and recurrence 人类胶质瘤从诊断到治疗和复发的多组学研究
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2025-12-11 DOI: 10.1016/j.ccell.2025.11.006
Hadeesha Piyadasa, Benjamin Oberlton, Mikaela Ribi, Ke Leow, Jolene S. Ranek, Inna Averbukh, Meelad Amouzgar, Candace C. Liu, Davide G. Franchina, Noah F. Greenwald, Erin F. McCaffrey, Rashmi Kumar, Selena Ferrian, Albert G. Tsai, Ferda Filiz, Christine Camacho Fullaway, Marc Bosse, Sricharan Reddy Varra, Alex Kong, Cameron Sowers, Michael Angelo
Gliomas are among the most lethal cancers, with limited treatment options. To uncover hallmarks of therapeutic escape and tumor microenvironment (TME) landscape, we applied spatial proteomics, transcriptomics, and glycomics to 670 lesions from 310 adult and pediatric patients. Single-cell analysis shows high B7H3+ tumor cell prevalence in glioblastoma (GBM) and pleomorphic xanthoastrocytoma, while most gliomas, including pediatric cases, express targetable tumor antigens in less than 50% of tumor cells, potentially explaining trial failures. Paired samples of isocitrate dehydrogenase (IDH)-mutant gliomas reveal recurrence driven by tumor-immune spatial reorganization, shifting from T cell and vasculature-associated myeloid cell-enriched niches to microglia and CD206+ macrophage-dominated tumors. Multi-omic integration identified N-glycosylation as the best classifier of grade, while the immune transcriptome best predicted GBM survival. Provided as a community resource, this study offers a framework for glioma targeting, classification, outcome prediction, and a baseline of TME composition across all stages.
胶质瘤是最致命的癌症之一,治疗选择有限。为了揭示治疗逃逸和肿瘤微环境(TME)景观的特征,我们应用空间蛋白质组学、转录组学和糖组学对310名成人和儿童患者的670个病变进行了研究。单细胞分析显示,B7H3+肿瘤细胞在胶质母细胞瘤(GBM)和多形性黄色星形细胞瘤中的患病率很高,而大多数胶质瘤,包括儿科病例,在不到50%的肿瘤细胞中表达可靶向的肿瘤抗原,这可能解释了试验失败的原因。异柠檬酸脱氢酶(IDH)突变胶质瘤的成对样本揭示了肿瘤免疫空间重组驱动的复发,从T细胞和血管相关的骨髓细胞富集壁龛转移到小胶质细胞和CD206+巨噬细胞主导的肿瘤。多组学整合鉴定n -糖基化是最好的分级器,而免疫转录组最能预测GBM的生存。作为一种社区资源,本研究为胶质瘤的靶向、分类、结果预测和所有阶段TME组成的基线提供了一个框架。
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引用次数: 0
Oncofetal reprogramming of malignant seeds and their ecosystem: Implications in clinical research 恶性种子的癌胎重编程及其生态系统:在临床研究中的意义
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2025-12-11 DOI: 10.1016/j.ccell.2025.11.010
Ankur Sharma, Mehak Gupta, Jacob George, Florent Ginhoux
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引用次数: 0
IL-36γ armored CAR T cells reprogram neutrophils to induce endogenous antitumor immunity IL-36γ装甲CAR - T细胞重编程中性粒细胞诱导内源性抗肿瘤免疫
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2025-12-11 DOI: 10.1016/j.ccell.2025.11.007
Yihan Zuo, David J. Vohwinkel, Bowen Dong, James R. McDowell, Brandon V. Guzman, Tharuna Sri Manickavel Pandian, Saborni Chattopadhyay, A.J.R. McGray, Scott H. Olejniczak, Joyce Ohm, Jianmin Wang, Mark D. Long, Eduardo Cortes Gomez, Terence J. Purdon, Wei Luo, Hemn Mohammadpour, Christopher S. Hackett, Leonid Cherkassky, Marco Davila, Scott I. Abrams, Renier J. Brentjens
Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors due to obstacles of antigen heterogeneity and the immunosuppressive tumor microenvironment (TME). Previous efforts focused on enhancing cytotoxicity and persistence of CAR T cells, while the feasibility of improving their therapeutic efficacy by leveraging the modulatory effects of CAR T cells on host anti-tumor immunity remains unclear. Here, we report that IL-36γ armored CAR T cells eradicate primary solid tumors and enable rejection of rechallenged antigen-negative tumors. IL-36γ armored CAR T cells favorably modulate the TME and reprogram unique neutrophil subsets with tumoricidal ability and antigen-(cross) presenting functions, resulting in the induction of endogenous T cells recognizing tumor antigens beyond CAR-targeted antigens. Our study demonstrates that neutrophil engagement by CAR T cells is a critical step in the establishment of the cancer-immunity cycle and introduces a broadly applicable method to overcome key barriers to adoptive cell therapies for solid tumors.
嵌合抗原受体(CAR) T细胞由于抗原异质性和免疫抑制肿瘤微环境(TME)的障碍,对实体肿瘤无效。以往的研究主要集中在增强CAR - T细胞的细胞毒性和持久性,而利用CAR - T细胞对宿主抗肿瘤免疫的调节作用来提高其治疗效果的可行性尚不清楚。在这里,我们报告IL-36γ装甲CAR - T细胞根除原发性实体瘤,并使抗原阴性肿瘤的再挑战排斥。IL-36γ装甲CAR- T细胞有利地调节TME和重编程独特的具有肿瘤杀伤能力和抗原(交叉)呈递功能的中性粒细胞亚群,导致诱导内源性T细胞识别肿瘤抗原,而不是CAR靶向抗原。我们的研究表明,CAR - T细胞与中性粒细胞的结合是建立癌症免疫周期的关键步骤,并引入了一种广泛适用的方法来克服实体瘤过继细胞治疗的关键障碍。
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引用次数: 0
Mapping the inflammatory origins of lung cancer 绘制肺癌炎症起源图
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2025-12-11 DOI: 10.1016/j.ccell.2025.11.005
Nobunari Sasaki, Mizuki Homme, Shunsuke Kitajima
How early precursor cells and their surrounding microenvironment cooperate to drive oncogenic progression in lung adenocarcinoma (LUAD) remains elusive. In this issue of Cancer Cell, Peng et al. conducted multimodal spatial-omics to comprehensively profile precancerous lung and LUAD tissues, uncovering alveolar progenitors and proinflammatory niches that co-evolve during cancer progression.
早期前体细胞及其周围微环境如何协同驱动肺腺癌(LUAD)的致癌进展仍然是一个谜。在这一期的Cancer Cell中,Peng等人通过多模态空间组学全面分析了癌前肺和LUAD组织,揭示了在癌症进展过程中共同进化的肺泡祖细胞和促炎利基。
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引用次数: 0
TROP-2-targeted antibody-drug conjugate SHR-A1921 for advanced or metastatic solid tumors: A first-in-human phase 1 study. trop -2靶向抗体-药物偶联物shrr - a1921用于晚期或转移性实体瘤:一项首次人体i期研究
IF 44.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2025-12-08 Epub Date: 2025-10-23 DOI: 10.1016/j.ccell.2025.09.012
Jia Zhong, Lin Wu, Zhengbo Song, Nianzeng Xing, Jiujie Cui, Xingya Li, Kailun Fei, Dihong Tang, Qi Dang, Liang Chen, Tianshu Liu, Caigang Liu, Yong Li, Shichuan Zhang, Xinghua Han, Juxiang Xiao, Feng Guo, Min Yan, Huiting Xu, Chunxiu Yuan, Jincai Zhong, Rongrui Liu, Xiujuan Qu, Shikai Wu, Shusuan Jiang, Yan Yang, Panpan Zhang, Hongqian Guo, Ce Wang, Qiushi Xie, Zhifei Lin, Shuni Wang, Jie Wang

This study is a first-in-human, three-stage, phase 1 trial (NCT05154604) designed to evaluate the trophoblast cell-surface antigen 2 (TROP-2)-targeted antibody-drug conjugate SHR-A1921 (1.5-6.0 mg/kg every 3 weeks) in 391 patients with pretreated advanced/metastatic solid tumors. Grade ≥3 treatment-related adverse events occurred in 132 patients (33.8%), with the most common being stomatitis, affecting 57 patients (14.6%). SHR-A1921 showed a low incidence of hematologic toxicities, with only 3.1% of patients experiencing grade ≥3 decreases in neutrophil count. The overall objective response rate was 24.8% (95% confidence interval [CI], 20.6-29.4), ranging from 18.2% to 43.1% across cohorts with platinum-resistant ovarian cancer, triple-negative breast cancer, small-cell lung cancer, non-small cell lung cancer, hormone receptor-positive breast cancer, cervical cancer, and biliary tract cancer. No significant correlation was found between TROP-2 expression and treatment efficacy. In summary, SHR-A1921 exhibited promising antitumor activity and a manageable safety profile, with 3.0 mg/kg every 3 weeks selected for further clinical development.

该研究是一项首次在人体内进行的三期i期试验(NCT05154604),旨在评估391例预先治疗的晚期/转移性实体瘤患者的TROP-2靶向抗体-药物偶联物SHR-A1921 (1.5-6.0 mg/kg / 3周)。132例患者(33.8%)发生≥3级治疗相关不良事件,最常见的是口腔炎,57例患者(14.6%)。SHR-A1921的血液学毒性发生率较低,只有3.1%的患者出现中性粒细胞计数≥3级下降。总体客观缓解率为24.8%(95%可信区间[CI], 20.6-29.4),在铂耐药卵巢癌、三阴性乳腺癌、小细胞肺癌、非小细胞肺癌、激素受体阳性乳腺癌、宫颈癌和胆道癌的队列中,总体客观缓解率为18.2% - 43.1%。TROP-2表达与治疗效果无显著相关性。总之,shrr - a1921表现出有希望的抗肿瘤活性和可管理的安全性,每3周3.0 mg/kg被选择用于进一步的临床开发。
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引用次数: 0
Functional pseudo-synapses: A new nexus in extracranial cancer. 功能性伪突触:颅外癌的新联系。
IF 44.5 1区 医学 Q1 CELL BIOLOGY Pub Date : 2025-12-08 Epub Date: 2025-10-23 DOI: 10.1016/j.ccell.2025.10.001
Xiaofei Zhi, Puran Zhang, Timothy C Wang

Functional cancer-to-neuron synapse-like connections are recognized as essential structures and hallmarks of both intracranial and extracranial tumors. In this issue of Cancer Cell, Ren et al. present high-resolution EM structures of pseudo-synaptic connections between sensory nerves and pancreatic ductal adenocarcinoma (PDAC).

功能性肿瘤与神经元突触样连接被认为是颅内和颅外肿瘤的基本结构和标志。在这一期的Cancer Cell中,Ren等人展示了感觉神经与胰腺导管腺癌(pancreatic ductal adencarcinoma, PDAC)之间伪突触连接的高分辨率EM结构。
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引用次数: 0
Tumor-initiating stem cells engineer immunity 肿瘤启动干细胞工程免疫
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2025-12-04 DOI: 10.1016/j.ccell.2025.10.012
Zhe Yang, Linheng Li
Immunotherapy reshapes the interaction between the tumor microenvironment and cancer stem cells. In this issue of Cancer Cell, Guo et al. revealed that SOX2High tumor-initiating stem cells reprogram neutrophils that block interferon-induced reprogramming after immunotherapy, maintaining their pro-tumor phenotype at the tumor-stroma interface.
免疫疗法重塑了肿瘤微环境与肿瘤干细胞之间的相互作用。在这一期的Cancer Cell中,Guo等人揭示了SOX2High肿瘤启动干细胞在免疫治疗后对中性粒细胞进行重编程,阻断干扰素诱导的重编程,在肿瘤-基质界面维持其促肿瘤表型。
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引用次数: 0
期刊
Cancer Cell
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