Cancer letters最新文献_第5页

HHLA2 promotes immune evasion in EGFR-mutant lung cancer by inhibiting CD8+ T cell glutamine metabolism via KIR3DL3 interaction HHLA2通过KIR3DL3相互作用抑制CD8+ T细胞谷氨酰胺代谢，促进egfr突变肺癌的免疫逃避。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-12 DOI: 10.1016/j.canlet.2025.218219

Fei Wu , Jiannan Shen , Zhiting Zhao , Yan Chen , Binhui Ren , Ming Li , Rong Yin , Yanyan Zhang , Shaorong Yu

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, and EGFR-mutant tumors show limited response to current immunotherapy. The immunosuppressive tumor microenvironment, particularly metabolic constraints on effector T cells, is increasingly recognized as a major barrier to effective anti-tumor responses. HHLA2, a B7 family member frequently elevated in EGFR-mutant NSCLC, has an incompletely defined role in immune escape. In this study, we demonstrate that tumor-derived HHLA2 engages the inhibitory receptor KIR3DL3 on CD8⁺ T cells, driving T cell exhaustion through metabolic reprogramming of amino acid utilization. HHLA2–KIR3DL3 signaling suppresses glutamine utilization through ERK/MAPK-dependent repression of SLC1A5, SLC38A2, and ADHFE1, key glutamine transporters and metabolic enzymes, thereby inducing metabolic insufficiency and dysfunctional cytokine production in CD8⁺ T cells, including reduced IFN-γ, TNF-α, and increased IL-10. Disruption of this axis—via HHLA2 deletion or antibody blockade—restored T cell metabolism and effector function, leading to attenuated tumor progression in humanized mouse models. Notably, HHLA2/KIR3DL3 inhibition synergized with EGFR tyrosine kinase inhibitors to enhance anti-tumor immunity and suppress tumor progression. Together, these findings identify HHLA2–KIR3DL3 as a key immunosuppressive pathway in EGFR-mutant NSCLC and may provide a rationale for therapeutic targeting to improve clinical outcomes.

非小细胞肺癌（NSCLC）仍然是癌症相关死亡的主要原因，egfr突变肿瘤对当前免疫治疗的反应有限。免疫抑制肿瘤微环境，特别是对效应T细胞的代谢限制，越来越被认为是有效抗肿瘤反应的主要障碍。HHLA2是一个B7家族成员，在egfr突变型NSCLC中经常升高，在免疫逃逸中的作用尚未完全确定。在这项研究中，我们证明了肿瘤来源的HHLA2与CD8+ T细胞上的抑制受体KIR3DL3结合，通过氨基酸利用的代谢重编程驱动T细胞衰竭。HHLA2-KIR3DL3信号通过ERK/ mapk依赖的SLC1A5、SLC38A2和ADHFE1（谷氨酰胺关键转运体和代谢酶）的抑制来抑制谷氨酰胺的利用，从而诱导CD8+ T细胞代谢不足和细胞因子产生功能失调，包括IFN-γ、TNF-α降低和IL-10升高。通过HHLA2缺失或抗体阻断破坏这条轴，恢复T细胞代谢和效应功能，导致人源化小鼠模型中肿瘤进展减弱。值得注意的是，HHLA2/KIR3DL3抑制与EGFR酪氨酸激酶抑制剂协同作用，增强抗肿瘤免疫，抑制肿瘤进展。总之，这些发现确定了HHLA2-KIR3DL3是egfr突变型非小细胞肺癌的关键免疫抑制途径，并可能为改善临床结果的靶向治疗提供理论依据。

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引用次数: 0

NCAPH promotes immune evasion via inhibiting PD-L1 protein degradation in head and neck squamous cell carcinoma NCAPH通过抑制头颈部鳞状细胞癌中PD-L1蛋白的降解促进免疫逃避。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-11 DOI: 10.1016/j.canlet.2025.218218

Baiyang Liu , Xudong Xiang , Yan Cheng , Jimin Fei , Mengge Wu , Laihao Qu , Xian Zhao , Xing Chen , Yao Li , Jia Du , Dengcai Mu , Haoqing Zhai , Qiushuo Shen , Yongbin Chen , Cuiping Yang

Head and neck squamous cell carcinoma (HNSCC) is an epithelial carcinoma characterized by its distinct geographical distribution, exhibiting a higher prevalence in Southeast Asia. Despite the approval of immune checkpoint blockade (ICB) therapy for treating advanced recurrent HNSCC, the extent of patient benefit remains limited. Elucidating the molecular regulatory mechanisms of immunosuppressive tumor microenvironment in HNSCC is crucial for improving current treatment status and patient outcomes. Our findings show that knockdown of NCAPH suppresses cell proliferation, migration, and xenograft tumor growth, while enhancing radiotherapy-induced cellular apoptosis. Importantly, we found that NCAPH binds to PD-L1 and disrupts its degradation, competing with HIP1R (Huntingtin-interacting protein 1-related) and leading to the stabilization of PD-L1 protein, which contributes to the formation of immunosuppressive tumor microenvironment. To inhibit the interaction between NCAPH and PD-L1, we created a peptide known as NPIDP (NCAPH and PD-L1 Interaction Disrupting Peptide) that effectively disrupts the interaction between NCAPH and PD-L1. Furthermore, topotecan, a well-characterized topoisomerase I inhibitor, was identified to bind NCAPH and promote its proteasomal degradation. Notably, we demonstrated that NPIDP and topotecan suppress tumor immune evasion both in vitro and in vivo. In summary, our findings reveal the critical role of NCAPH in regulating tumor immune surveillance, suggesting that NCAPH could serve as a potential biomarker and therapeutic target for HNSCC in the future.

头颈部鳞状细胞癌（HNSCC）是一种具有独特地理分布特征的上皮性癌，在东南亚表现出较高的患病率。尽管免疫检查点阻断（ICB）疗法被批准用于治疗晚期复发性HNSCC，但患者受益的程度仍然有限。阐明HNSCC免疫抑制肿瘤微环境的分子调控机制对改善当前治疗状况和患者预后至关重要。我们的研究结果表明，NCAPH的下调抑制了细胞增殖、迁移和异种移植肿瘤的生长，同时增强了放疗诱导的细胞凋亡。重要的是，我们发现NCAPH与PD-L1结合并破坏其降解，与HIP1R（亨廷顿蛋白相互作用蛋白1相关）竞争，导致PD-L1蛋白稳定，从而有助于形成免疫抑制性肿瘤微环境。为了抑制NCAPH和PD-L1之间的相互作用，我们创造了一种名为NPIDP （NCAPH和PD-L1相互作用干扰肽）的肽，它有效地破坏了NCAPH和PD-L1之间的相互作用。此外，拓扑替康（topotecan）是一种表征良好的拓扑异构酶I抑制剂，可以结合NCAPH并促进其蛋白酶体降解。值得注意的是，我们证明了NPIDP和拓扑替康在体外和体内都抑制肿瘤免疫逃避。总之，我们的研究结果揭示了NCAPH在调节肿瘤免疫监视中的关键作用，表明NCAPH可以作为未来HNSCC的潜在生物标志物和治疗靶点。

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引用次数: 0

Progressive lesion type is predictive of post-progression survival in first-line chemoimmunotherapy for Non-Small Cell Lung Cancer 进展性病变类型预测非小细胞肺癌一线化疗免疫治疗的进展后生存

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-10 DOI: 10.1016/j.canlet.2025.218191

Yuan Gao , Lee X. Li , Andrew Rowland , Christos S. Karapetis , Natalie Parent , Ganessan Kichenadasse , Ashley M. Hopkins , Michael J. Sorich

引用次数: 0

Overcoming EGFR TKI resistance and immunosuppression in non-small cell lung cancer via EGFR/TLR9/PD-L1 triple-targeted therapy 通过EGFR/TLR9/PD-L1三重靶向治疗克服非小细胞肺癌EGFR TKI耐药和免疫抑制

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-10 DOI: 10.1016/j.canlet.2025.218217

Wan-Ying Zhang, Zi-Qi Wang, Xing-Xing Fan

引用次数: 0

Extrachromosomal DNA amplifications exhibit distinct molecular characteristics and prognostic implications in gastric cancer 染色体外DNA扩增在胃癌中表现出独特的分子特征和预后意义。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-09 DOI: 10.1016/j.canlet.2025.218214

Seunghyun Kang , Donghyeok Seol , Jieun Lee , Chanmi Bang , Mira Yoo , Soyeon Kim , Sepil An , Hyeongjin Cho , Duyeong Hwang , So Hyun Kang , Young Suk Park , Sang-Hoon Ahn , Hyung-Ho Kim , Eunhee Yi , Sanghyun Kim , Yun-Suhk Suh , Hoon Kim

Gastric cancer (GC) is characterized by marked molecular heterogeneity that contributes to differential patient outcomes. Focal amplification in form of extrachromosomal DNA (ecDNA) is common in multiple cancer types and is associated with poor patient outcomes, but its prevalence and clinical implications in GC remain largely unclear. In this study, we analyzed whole genome and whole transcriptome sequencing from 76 GC patients collected at a single hospital (Seoul National University Bundang Hospital) in Korea. EcDNAs were detected in 22.4 % (n = 17) of GC patients. Notably, 75.0 % (n = 12) of the patients in the ‘chromosomal instability (CIN)’ category carried ecDNAs which frequently co-occurred with chromothripsis. We found that ecDNAs were enriched for known cancer genes, and the presence of ecDNAs was associated with poor patient prognosis. Among the CIN cases, patients carrying ecDNAs showed gene expression patterns related to chromosomal instability, as also observed in patients having only non-ecDNA chromosomal amplicons (ChAmp) but exhibited more pronounced immune suppression. Our findings show that ecDNAs display distinct molecular characteristics in GC, including the high prevalence of cancer genes and pronounced characteristic of immune suppression, alongside clinical implications, suggesting that ecDNA is a key molecular factor in the clinical management of GC patients, particularly for the CIN subtype patients.

胃癌（GC）的特点是显著的分子异质性，这导致了患者预后的差异。染色体外DNA （ecDNA）形式的局灶性扩增在多种癌症类型中很常见，并与不良患者预后相关，但其在胃癌中的患病率和临床意义仍不清楚。在这项研究中，我们分析了在韩国一家医院（首尔国立大学盆唐医院）收集的76例胃癌患者的全基因组和全转录组测序。22.4% （n=17）的GC患者检测到ecdna。值得注意的是，75.0% （n=12）的“染色体不稳定（CIN）”患者携带的ecdna经常与染色体断裂同时发生。我们发现已知癌症基因的ecDNAs富集，并且ecDNAs的存在与患者预后不良相关。在CIN病例中，携带ecdna的患者表现出与染色体不稳定性相关的基因表达模式，在只有非ecdna染色体扩增子（ChAmp）但表现出更明显的免疫抑制的患者中也观察到这一点。我们的研究结果表明，ecDNA在胃癌中表现出独特的分子特征，包括癌基因的高流行率和明显的免疫抑制特征，以及临床意义，这表明ecDNA是胃癌患者临床管理的关键分子因素，特别是对于CIN亚型患者。

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引用次数: 0

High-fat diet induced ECM remodeling attenuates chemosensitivity in prostate cancer via activating Piezo1-dependent mitochondria-ER contacts 高脂肪饮食诱导的ECM重塑通过激活piezo1依赖性线粒体-内质网接触来减弱前列腺癌的化疗敏感性。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-09 DOI: 10.1016/j.canlet.2025.218204

Yupeng Guan , Fei Cao , Yusheng Luo , Jun Li , Peng Wu , Junfu Zhang , Wenhan Qiu , Shaohong Lai , Hanqi Lei , Jun Pang

High-fat diet (HFD) and obesity are established risk factors for therqpy resistance in prostate cancer (PCa), but the underlying mechanisms remain incompletely understood. Here, we demonstrate that a HFD promote chemoresistance by remodeling the tumor microenvironment (TME) and activating extracellular matrix (ECM)-dependent mitochondria-endoplasmic reticulum contacts (MERCs). Through integration of clinical data with multi-omics and biomechanical analyses, we show that lipid-overloaded tumor cells secrete TGF-β1 to indirectly drive the activation of cancer-associated fibroblasts (CAFs). This triggers pathological ECM stiffening and collagen deposition. These biomechanical alterations are sensed by the mechanosensor Piezo1, which transduces pro-malignant signals that foster chemoresistance. Pharmacological inhibition of Piezo1 blocks its channel activity, disrupts intracellular ion homeostasis and consequently induces MERCs dissociation. MERCs disassembly, in return, destabilizes the IP3R-GRP75-VDAC complex, leading to metabolic reprogramming characterized by mitochondrial dysfunction, endoplasmic reticulum stress, and redox imbalance. Crucially, dual targeting of lipid metabolism (with statins) and mechanotransduction (with GsMTx4) resensitizes PCa to chemotherapy by normalizing ECM architecture and restoring MERCs integrity. Our work defines the "mechanometabolic niche" as a targetable signaling hub where coordinated lipid metabolism and TME biomechanics converge to dictate therapeutic response and unveils a novel co-targeting strategy for advanced PCa.

高脂肪饮食（HFD）和肥胖是前列腺癌（PCa）治疗耐药的确定危险因素，但其潜在机制尚不完全清楚。在这里，我们证明了HFD通过重塑肿瘤微环境（TME）和激活细胞外基质（ECM）依赖的线粒体-内质网接触（MERCs）来促进化疗耐药。通过将临床数据与多组学和生物力学分析相结合，我们发现脂质超载的肿瘤细胞分泌TGF-β1间接驱动癌症相关成纤维细胞（CAFs）的激活。这引发病理性ECM硬化和胶原沉积。这些生物力学变化被机械传感器Piezo1感知，它可以传递促进化学耐药性的恶性信号。药理抑制Piezo1阻断其通道活性，破坏细胞内离子稳态，从而诱导merc解离。反过来，MERCs的分解破坏了IP3R-GRP75-VDAC复合物的稳定性，导致代谢重编程，其特征是线粒体功能障碍、内质网应激和氧化还原失衡。至关重要的是，脂质代谢（使用他汀类药物）和机械转导（使用GsMTx4）的双重靶向通过使ECM结构正常化和恢复merc完整性，使PCa对化疗重新敏感。我们的工作将“机械代谢利基”定义为一个可靶向的信号中枢，在这里协调脂质代谢和TME生物力学汇聚在一起，决定治疗反应，并揭示了一种针对晚期前列腺癌的新型共同靶向策略。

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引用次数: 0

Tumor microenvironment in glioblastoma: The central role of the hypoxic–necrotic core 胶质母细胞瘤的肿瘤微环境：缺氧坏死核心的核心作用。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-09 DOI: 10.1016/j.canlet.2025.218216

Clara Bayona , Teodora Ranđelović , Ignacio Ochoa

Glioblastoma (GBM), the most aggressive and lethal primary brain tumor, is characterized by profound intratumoral heterogeneity and a hostile tumor microenvironment (TME) that drives immune evasion, therapeutic resistance, and relentless progression. Among its defining pathological features is the development of a hypoxic–necrotic core, long recognized as a hallmark of poor clinical outcome. This review synthesizes current insights into how hypoxia and necrosis act not merely as pathological markers, but as a spatiotemporal evolution engine of the GBM TME, driving metabolic adaptation, extracellular matrix (ECM) remodeling, and immune evasion. We examine how oxygen and nutrient deprivation activate hypoxia-inducible factors (HIFs), triggering cascades that promote angiogenesis, altered metabolism, and accumulation of immunosuppressive metabolites. These stressors also contribute to the recruitment and polarization of tumor-associated macrophages (TAMs) and neutrophils (TANs), expansion of myeloid-derived suppressor cells (MDSCs), and infiltration of regulatory T cells (Tregs), collectively creating an immune-excluded niche. Furthermore, hypoxia-induced ECM stiffening and degradation enhance tumor invasiveness while limiting immune cell access. By exploring the dynamic interplay between physicochemical stressors and immune modulation within the necrotic core, this review highlights the need for targeting the hypoxia-necrosis axis to overcome current therapeutic limitations. A deeper understanding of these processes will be crucial for the development of precision-targeted therapies in this highly refractory malignancy.

胶质母细胞瘤（GBM）是最具侵袭性和致死性的原发性脑肿瘤，其特点是具有深刻的肿瘤内异质性和敌对的肿瘤微环境（TME），可驱动免疫逃避、治疗抵抗和无情的进展。其明确的病理特征之一是核心缺氧坏死的发展，长期以来被认为是不良临床结果的标志。这篇综述综合了目前关于缺氧和坏死如何不仅作为病理标记，而且作为GBM TME的时空进化引擎，驱动代谢适应，细胞外基质（ECM）重塑和免疫逃避的见解。我们研究了缺氧和营养剥夺如何激活缺氧诱导因子（hif），触发级联反应，促进血管生成，改变代谢和免疫抑制代谢物的积累。这些应激源还有助于肿瘤相关巨噬细胞（tam）和中性粒细胞（tan）的募集和极化，髓源性抑制细胞（MDSCs）的扩增和调节性T细胞（Tregs）的浸润，共同形成免疫排斥生态位。此外，缺氧诱导的ECM硬化和降解增强了肿瘤侵袭性，同时限制了免疫细胞的进入。通过探索坏死核心内物理化学应激源和免疫调节之间的动态相互作用，本综述强调需要针对缺氧-坏死轴来克服当前的治疗局限性。对这些过程的深入了解将对这种高度难治性恶性肿瘤的精确靶向治疗的发展至关重要。

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引用次数: 0

BTSCs exosomes derived NamiRNA-enhancer network of miR-151a-3p mediates a positive feedback loop and promotes the progression of glioma via FAK phosphorylation btsc外泌体衍生的miR-151a-3p的namirna增强子网络介导一个正反馈回路，并通过FAK磷酸化促进胶质瘤的进展。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-09 DOI: 10.1016/j.canlet.2025.218211

Zhou Qi , Yinian Zhang , Ye Gong , Chen Liang , Qingping Zhang , Yaling Chen , Mingrui Zhao , Binbin Zhang , Zhiyong Liu , Beichen Zhang , Jian Li , Jianli Liu , Yawen Pan , Shiwen Guo

Glioblastoma (GBM) is a highly invasive and treatment-resistant brain tumour, with recurrence often driven by the persistence of brain tumour stem cells (BTSCs). Recent evidence suggests that BTSC-derived exosomes, particularly under hypoxic conditions, play a critical role in GBM progression by facilitating intercellular communication and enhancing tumour invasiveness; however, the precise molecular mechanisms remain unclear. We demonstrated that hypoxic BTSCs (H-BTSCs) influence glioma cells through the transfer of exosomes. High-throughput sequencing revealed a marked increase in miR-151a-3p expression under hypoxic. Mechanistically, miR-151a-3p functions within a nuclear-activating miRNA (NamiRNA)-enhancer network: P300 acetylates PDE4D, and H3K27ac-dependent binding to the PDE4D promoter upregulates Focal Adhesion Kinase (FAK)/Yes-Associated Protein (YAP) signaling in GBM cells. CRISPR/Cas9-mediated deletion of the PDE4D enhancer confirmed that miR-151a-3p's function is enhancer dependent. Both in vitro and in vivo experiments demonstrated that exosomal miR-151a-3p promotes glioma cell migration, invasion, proliferation, and epithelial‒mesenchymal transition, thereby increasing tumour aggressiveness. These findings highlight the NamiR-151a-3p/PDE4D/FAK/YAP axis as a promising therapeutic target for GBM.

胶质母细胞瘤（GBM）是一种高度侵袭性和治疗耐药的脑肿瘤，其复发通常由脑肿瘤干细胞（BTSCs）的持续存在驱动。最近的证据表明，btsc衍生的外泌体，特别是在缺氧条件下，通过促进细胞间通讯和增强肿瘤侵袭性，在GBM进展中起关键作用；然而，确切的分子机制尚不清楚。我们证明了缺氧BTSCs （H-BTSCs）通过外泌体的转移影响胶质瘤细胞。高通量测序显示，缺氧条件下miR-151a-3p的表达显著增加。在机制上，miR-151a-3p在核激活miRNA （NamiRNA）增强子网络中起作用：P300乙酰化PDE4D， h3k27ac依赖于PDE4D启动子的结合上调GBM细胞中的Focal Adhesion Kinase (FAK)/ yeh - associated Protein （YAP）信号。CRISPR/ cas9介导的PDE4D增强子缺失证实了miR-151a-3p的功能依赖于增强子。体外和体内实验均表明，外泌体miR-151a-3p促进胶质瘤细胞迁移、侵袭、增殖和上皮-间质转化，从而增加肿瘤的侵袭性。这些发现突出了NamiR-151a-3p/PDE4D/FAK/YAP轴作为GBM的一个有希望的治疗靶点。

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引用次数: 0

Fgl2-knockout tumor cells serve as a vaccine inducing long-duration brain-resident memory T cells that reject subsequent intracranial tumor cell challenges fgl2敲除肿瘤细胞可作为一种疫苗，诱导长时间脑驻留记忆T细胞，拒绝随后颅内肿瘤细胞的攻击。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-09 DOI: 10.1016/j.canlet.2025.218215

Sheng Zhang , Yining Jin , Zhiliang Jia , Xueqing Xia , Yang Li , Qi Wang , Jing Wang , Jian Wang , Joya Chandra , Gregory K. Friedman , Shulin Li

The failure to prevent brain tumors, including both recurrent primary and metastatic brain tumors, is the primary cause of patients’ mortality. We developed a novel whole tumor-cell vaccine to rapidly induce long-duration brain-resident memory T (T_RM) cells that prevent brain tumor progression. Ten Fgl2-KO primary and metastatic tumor cell lines, generated via CRISPR/Cas9, were used to vaccinate mice and for intracranial challenges with the WT tumor cells. Not only did vaccinated mice reject these tumor cell challenges, but also more than half of these mice became long-duration survivors. Transplanting brain immune cells from vaccinated mice into naïve mice enabled this rejection of intracranial challenges in the recipient mice, whereas depleting T_RM cells impaired it. Mechanistic studies uncovered that Fgl2 KO impaired the immunosuppressive molecule CD47; reconstitution of CD47 expression in Fgl2-KO tumor cells reversed the protection. Likewise, vaccination with CD47-knockdown tumor cells produced similar effects. Proteomic analysis found that Fgl2-KO–mediated suppression of CD47 occurred through the Src and PKCα pathways; inhibition of either pathway reduced CD47 expression. This study is the first to show that disrupting the Fgl2-CD47 circuit in tumor cells impairs their tumorigenic properties and induces long-term brain T_RM cells, thereby providing new strategies for improving the efficacy of currently used whole tumor-cell vaccines.

未能预防脑肿瘤，包括复发性原发性和转移性脑肿瘤，是患者死亡的主要原因。我们开发了一种新的全肿瘤细胞疫苗，可以快速诱导长时间脑驻留记忆T （TRM）细胞，防止脑肿瘤进展。通过CRISPR/Cas9生成的10个Fgl2-KO原发和转移肿瘤细胞系用于小鼠接种和WT肿瘤细胞的颅内攻击。接种疫苗的小鼠不仅拒绝了这些肿瘤细胞的攻击，而且这些小鼠中有一半以上成为长期幸存者。将接种疫苗小鼠的脑免疫细胞移植到naïve小鼠体内，使受体小鼠对颅内挑战的排斥反应得以实现，而消耗TRM细胞则使其受损。机制研究发现Fgl2 KO破坏免疫抑制分子CD47；Fgl2-KO肿瘤细胞中CD47表达的重建逆转了这种保护作用。同样，用敲低cd47的肿瘤细胞接种疫苗也产生了类似的效果。蛋白质组学分析发现fgl2 - ko介导的CD47抑制通过Src和PKCα途径发生；抑制任一途径均可降低CD47的表达。这项研究首次表明，破坏肿瘤细胞中的Fgl2-CD47通路会损害肿瘤细胞的致瘤特性并诱导长期脑TRM细胞，从而为提高目前使用的全肿瘤细胞疫苗的疗效提供了新的策略。

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引用次数: 0

HP1 enhances radio- and chemotherapy resistance in osteosarcoma via PARP1-dependent transcriptional repression and HR repair HP1通过parp1依赖的转录抑制和HR修复增强骨肉瘤的放疗和化疗耐药性。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-08 DOI: 10.1016/j.canlet.2025.218213

Yuanxin Zhu , Wenjia Li , Yuntan Qiu , Zhihuai Deng , Yu Li , Hengxing Chen , Jingyuan Zhang , Daning Lu , Kaishun Hu , Dongsheng Huang , Dong Yin

Osteosarcoma is a primary malignant bone tumour with an unsatisfactory prognosis, and individualised and comprehensive treatment is needed. HP1 (α/β/γ) is an important heterochromatin protein involved in transcriptional regulation and is also involved in the DNA damage response (DDR). However, little is known about the participation of HP1 in DNA damage-induced transcriptional repression. In this study, HP1 proteins were shown to be involved in DNA damage-mediated transcriptional repression at the very onset of DNA damage. Mechanistically, HP1 proteins were recruited to DNA damage sites by interacting with and being covalently PARylated by PARP1. This process increased H2AK119Ub, which ultimately led to the inactivation of RNA Pol II to achieve transcriptional suppression. Silencing HP1 led to a weakening of PARP1 recruitment and homologous recombination (HR) repair. Concurrently, HP1γ (CBX3) knockdown resulted in an increased the sensitivity of osteosarcoma cells to radiotherapy, chemotherapy and PARP1 inhibitors. The results of the study demonstrated the involvement of HP1 in the DDR via covalent PARylation by PARP1, resulting in the suppression of transcription and the promotion of HR repair. Overall, these results identify a new molecular mechanism of DNA damage-induced transcriptional repression and provide a theoretical basis for the potential application of DNA damage-induced transcriptional repression in the treatment of osteosarcoma.

骨肉瘤是一种预后不佳的原发性恶性骨肿瘤，需要个体化和综合治疗。HP1 （α/β/γ）是参与转录调控的重要异染色质蛋白，也参与DNA损伤反应（DDR）。然而，关于HP1参与DNA损伤诱导的转录抑制知之甚少。在这项研究中，HP1蛋白被证明在DNA损伤开始时参与DNA损伤介导的转录抑制。机制上，HP1蛋白通过与PARP1相互作用并被PARP1共价聚合而被招募到DNA损伤位点。这一过程增加H2AK119Ub，最终导致RNA Pol II失活，从而实现转录抑制。沉默HP1导致PARP1募集和同源重组（HR）修复的减弱。同时，HP1γ (CBX3)敲低导致骨肉瘤细胞对放疗、化疗和PARP1抑制剂的敏感性增加。研究结果表明，HP1通过PARP1的共价PARylation参与DDR，从而抑制转录并促进HR修复。总的来说，这些结果确定了DNA损伤诱导的转录抑制的新的分子机制，并为DNA损伤诱导的转录抑制在骨肉瘤治疗中的潜在应用提供了理论基础。

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引用次数: 0