Cancer letters最新文献_第10页

lncDDR suppresses drug resistance by regulating DNA damage repair through ILF2-YB1 in T-cell acute lymphoblastic leukemia lncDDR通过ILF2-YB1调节t细胞急性淋巴细胞白血病的DNA损伤修复，从而抑制耐药性。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-16 DOI: 10.1016/j.canlet.2025.218210

Kegan Zhu , Haiyang Zhang , Guoli Li , Suyu Zong , Xue Han , Miaomiao Zhang , Yingchi Zhang , Ming Gao , Wenyu Yang , Zhi Yao , Zhe Liu

T-cell acute lymphoblastic leukemia (T-ALL) is a prevalent hematologic malignancy in pediatric and adolescent populations, characterized by uncontrolled proliferation of immature T lymphocytes. The development of chemoresistance represents a major clinical challenge in T-ALL treatment and alteration in DNA damage response (DDR) pathways was recognized as important mechanism underlying drug resistance. Long non-coding RNAs (lncRNAs), defined as transcripts exceeding 200 nucleotides in length, have emerged as critical regulators in various pathological processes, including oncogenesis. However, their specific roles in DDR regulation within T-ALL remain largely unexplored. In this study, through comprehensive sequencing analysis of clinical specimens, we identified that lncDDR was significantly upregulated in T-ALL patients. Functional characterization revealed that lncDDR promotes leukemogenesis by enhancing tumor cell proliferation both in vitro and in vivo. Utilizing RNA pull-down assays coupled with mass spectrometric analysis, we identified ILF2 (interleukin enhancer-binding factor 2) as a direct interacting partner of lncDDR. Given the established involvement of ILF2 in DDR processes, we subsequently investigated the functional role of lncDDR in modulating DDR pathways in T-ALL. Additionally, we systematically evaluated the impact of lncDDR on chemosensitivity in T-ALL treatment.

T细胞急性淋巴细胞白血病（T- all）是儿童和青少年人群中普遍存在的一种血液恶性肿瘤，其特征是未成熟T淋巴细胞不受控制的增殖。化疗耐药的发展是T-ALL治疗的主要临床挑战，DNA损伤反应（DDR）途径的改变被认为是耐药的重要机制。长链非编码rna （lncRNAs）被定义为长度超过200个核苷酸的转录本，在包括肿瘤发生在内的各种病理过程中已成为关键的调节因子。然而，它们在T-ALL中DDR调节中的具体作用在很大程度上仍未被探索。在本研究中，通过对临床标本的全面测序分析，我们发现lncDDR在T-ALL患者中显著上调。功能表征表明，lncDDR通过体外和体内增强肿瘤细胞增殖来促进白血病的发生。利用RNA下拉试验和质谱分析，我们确定ILF2（白细胞介素增强因子结合因子2）是lncDDR的直接相互作用伙伴。鉴于ILF2参与了DDR过程，我们随后研究了lncDDR在T-ALL中调节DDR通路中的功能作用。此外，我们系统地评估了lncDDR对T-ALL治疗中化疗敏感性的影响。

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引用次数: 0

A timeless chronicle: Effects of cigarette smoke on GPR15 receptor and its oncogenic potential 永恒的编年史：香烟烟雾对GPR15受体的影响及其致癌潜力。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-16 DOI: 10.1016/j.canlet.2025.218224

Poompozhil Mathivanan , Pratima Raut , Neelanjana Gayen , Apar K. Ganti , Moorthy P. Ponnusamy , Surinder K. Batra

G-protein-coupled receptors (GPCRs) represent the largest family of membrane receptors encoded in the human genome, with diverse physiological and pathological functions. GPR15, a recently characterized member of this family, has emerged as a receptor of interest due to its significant upregulation and hypomethylation in response to cigarette smoking, a modifiable environmental risk factor implicated in numerous diseases. Initially, it was identified as a coreceptor for viruses, human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). It was later deorphanized with the discovery of its endogenous ligand, C10orf99. This review explores the effect of cigarette smoke on GPR15 expression, its different ligands, and the GPR15 signaling axis in various smoking-related cancers, such as lung, gastric, pancreatic, bladder, and colorectal cancers.

g蛋白偶联受体（gpcr）是人类基因组中编码的最大的膜受体家族，具有多种生理和病理功能。GPR15是该家族最近发现的一个成员，由于其在吸烟反应中显著上调和低甲基化，已成为一种感兴趣的受体，这是一种可改变的环境风险因素，与许多疾病有关。最初，它被确定为病毒的辅助受体，人类免疫缺陷病毒（HIV）和猿猴免疫缺陷病毒（SIV）。后来，随着内源性配体C10orf99的发现，它被去孤儿化了。这篇综述探讨了香烟烟雾对GPR15表达、其不同配体和GPR15信号轴在各种吸烟相关癌症（肺癌、胃癌、胰腺癌、膀胱癌和结直肠癌）中的影响。

引用次数: 0

Foundation models in clinical oncology: Progresses and perspectives 临床肿瘤学基础模型：进展与展望。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-15 DOI: 10.1016/j.canlet.2025.218220

Jing Li , Jing Fu , Xin Geng , Hongyang Wang

Cancer remains a leading global burden, and the volume of multimodal oncology data—spanning digital pathology, radiology, genomics, and Electronic Health Records (EHRs)—is expanding exponentially. Foundation models (FMs), trained on broad unlabeled corpora and adapted to diverse tasks, have catalyzed advances in screening and diagnosis, outcome prediction, and inference of actionable molecular alterations, with early traction in treatment selection, drug repurposing, and clinical trial design. Yet key barriers persist: variability in tissue processing, imaging protocols, and data standards drives heterogeneity; the scarcity of well-annotated, multi-institutional cohorts limits development and independent validation; regulatory guidelines and policy making for FM-enabled diagnostics are still maturing; privacy and data sovereignty complicate data sharing; and bias against under-represented populations threatens equitable performance. A practical way forward is to combine high-quality, representative cohorts and interoperable data infrastructure with cross-institutional partnerships that embed AI talent within clinical teams—closing these gaps and enabling generalizable, trustworthy tools to reshape cancer care.

癌症仍然是一个主要的全球负担，多模式肿瘤学数据（包括数字病理学、放射学、基因组学和电子健康记录）的数量正在呈指数级增长。基础模型（FMs）在广泛的未标记的语料库上训练并适应不同的任务，催化了筛选和诊断、结果预测和可操作分子改变的推断方面的进展，在治疗选择、药物重新利用和临床试验设计方面具有早期牵引力。然而，关键的障碍仍然存在：组织处理、成像协议和数据标准的可变性导致了异质性；缺乏良好注释的多机构队列限制了开发和独立验证；支持fm诊断的监管指南和政策制定仍在成熟；隐私和数据主权使数据共享复杂化；对代表性不足的人群的偏见会威胁到公平的表现。一种可行的方法是将高质量、具有代表性的队列和可互操作的数据基础设施与跨机构合作伙伴关系结合起来，将人工智能人才嵌入临床团队中，从而缩小这些差距，并启用可推广、可信赖的工具来重塑癌症治疗。

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引用次数: 0

Roles and therapeutic targeting of SLC transporters in gastrointestinal malignancies SLC转运体在胃肠道恶性肿瘤中的作用和治疗靶点。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-15 DOI: 10.1016/j.canlet.2025.218222

Junshu Wang , Xiaoyu Huang , Shuyi Chen , Yuanci Zhang , Ge Miao , Shuya Du , Xin Wang , Yuanyuan Lu , Xiaodi Zhao

The solute carrier (SLC) transporter family, serving as metabolic gatekeepers, transports a range of substrates (nutrients, metabolites, ions, drugs) and regulates key physiological processes (proliferation, migration, angiogenesis, chemoresistance, immunomodulation, energy metabolism). Gastrointestinal malignancies are a leading cause of cancer-related deaths globally, marked by high prevalence and aggressive growth. Metabolic reprogramming, as an emerging cancer hallmark, promotes uncontrolled tumour proliferation. It dynamically adjusts the distribution of nutrients and energy in the tumour microenvironment, thereby regulating specific cellular processes. SLC transporters are widely expressed in the gastrointestinal tract, and their dysfunction can significantly affect tumour growth. Understanding the complex crosstalk between SLCs, cancer cell metabolism, and the tumour microenvironment is crucial for developing novel therapies. This review summarises the roles of SLCs in various oncogenic behaviours of gastrointestinal tumors, explains how their expression patterns and genetic variations contribute to chemoresistance, and assesses the clinical value of targeting SLC family proteins for therapeutic purposes.

溶质载体（SLC）转运蛋白家族作为代谢看门人，运输一系列底物（营养物质、代谢物、离子、药物）并调节关键的生理过程（增殖、迁移、血管生成、化学耐药、免疫调节、能量代谢）。胃肠道恶性肿瘤是全球癌症相关死亡的主要原因，其特点是发病率高，生长迅速。代谢重编程，作为一个新兴的癌症标志，促进不受控制的肿瘤增殖。它动态地调节肿瘤微环境中营养物质和能量的分布，从而调节特定的细胞过程。SLC转运蛋白在胃肠道中广泛表达，其功能障碍可显著影响肿瘤生长。了解SLCs，癌细胞代谢和肿瘤微环境之间的复杂串扰对于开发新疗法至关重要。这篇综述总结了SLC在胃肠道肿瘤的各种致癌行为中的作用，解释了它们的表达模式和遗传变异如何促进化疗耐药，并评估了靶向SLC家族蛋白的临床治疗价值。

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引用次数: 0

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