Cancer letters最新文献_第7页

Lidocaine potentiates thermal ablation in cholangiocarcinoma by modulating TRPV6-Driven Ca2+/PI3K/AKT/HSF-1 signaling pathway 利多卡因通过调节trpv6驱动的Ca2+/PI3K/AKT/HSF-1信号通路增强胆管癌的热消融

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-18 DOI: 10.1016/j.canlet.2025.218226

Ping-ping Chen , Yun-kai Lin , Ming-xing Xia , Hui-bo Feng , Yu-fei Pan , Ye-xiong Tan , Meng-you Xu , Xin-hao Xing , Xiao-meng Yao , Bing Hu , Hong-yang Wang , Wen-hao Qin , Li-wei Dong

Sublethal heat stress during thermal ablation induces thermotolerance and tumor recurrence, limiting its efficacy in cholangiocarcinoma (CCA). Here, we reported that lidocaine, a commonly used local anesthetic, acts as a thermosensitizer by directly targeting TRPV6, an ion channel overexpressed in CCA and correlated with poor prognosis. In CCA models, lidocaine enhanced heat-induced apoptosis and suppressed proliferation. Mechanistically, it selectively inhibited TRPV6-mediated store-operated calcium entry (SOCE), disrupting the Ca²⁺/PI3K/AKT/HSF-1 signaling axis, suppressing HSF-1 nuclear translocation, and downregulating cytoprotective HSP70. Direct binding between lidocaine and TRPV6 was confirmed by surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS). Molecular dynamics simulations and mutagenesis identified TRP583 as the critical binding residue; its mutation abolished lidocaine-induced calcium inhibition and thermal sensitization. In vivo, lidocaine combined with ablation significantly reduced tumor growth and recurrence. Our results establish TRPV6 as a functional target of lidocaine and provide a mechanistic basis for repurposing this anesthetic as an ablation sensitizer in CCA. This strategy offers a clinically applicable approach to overcome tumor thermotolerance and enhance the efficacy of thermal ablation in cholangiocarcinoma.

热消融过程中的亚致死热应激诱导热耐受性和肿瘤复发，限制了其在胆管癌（CCA）中的疗效。在这里，我们报道了利多卡因，一种常用的局部麻醉剂，通过直接靶向TRPV6作为热敏剂，TRPV6是一种在CCA中过度表达的离子通道，与不良预后相关。在CCA模型中，利多卡因增强热诱导的细胞凋亡，抑制细胞增殖。在机制上，它选择性地抑制trpv6介导的储存操作钙进入（SOCE），破坏Ca2+/PI3K/AKT/HSF-1信号轴，抑制HSF-1核易位，下调细胞保护性HSP70。通过表面等离子体共振（SPR）、细胞热移测定（CETSA）和药物亲和力反应靶稳定性（DARTS）证实了利多卡因与TRPV6的直接结合。分子动力学模拟和诱变鉴定TRP583为关键结合残基；它的突变消除了利多卡因诱导的钙抑制和热敏化。在体内，利多卡因联合消融术显著降低肿瘤生长和复发。我们的研究结果确立了TRPV6作为利多卡因的功能靶点，并为这种麻醉剂在CCA中作为消融增敏剂的用途提供了机制基础。该策略为克服肿瘤热耐受性，提高热消融治疗胆管癌的疗效提供了一种临床适用的方法。

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引用次数: 0

Corrigendum to “Identification of metastasis-associated proteins involved in gallbladder carcinoma metastasis by proteomic analysis and functional exploration of chloride intracellular channel 1” [Cancer Lett. 281 (2009) 71–81] “通过蛋白质组学分析和细胞内氯离子通道1的功能探索鉴定胆囊癌转移相关蛋白”[癌症杂志]，281(2009)71-81]。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-17 DOI: 10.1016/j.canlet.2025.218201

Jian-Wei Wang , Shu-You Peng , Jiang-Tao Li , Yong Wang , Zhi-Ping Zhang , Yan Cheng , De-Qing Cheng , Wei-Hong Weng , Xiang-Song Wu , Xiao-Zhou Fei , Zhi-Wei Quan , Ji-Yu Li , Song-Gang Li , Ying-Bin Liu

引用次数: 0

Consensus on the diagnosis and treatment of unresectable stage III driver gene-positive non-small cell lung cancer 不可切除的III期驱动基因阳性非小细胞肺癌的诊断和治疗共识。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-17 DOI: 10.1016/j.canlet.2025.218223

Xiangjiao Meng , Nan Bi , Jun Wang , Xue Meng , Jianbo Wang , Ligang Xing , Yufeng Cheng , Shun Lu , Ming Chen , Jinming Yu , Chinese Society of Clinical Oncology (CSCO) Radiation Therapy Expert Committee, Consensus Expert Group

Unresectable stage III non-small cell lung cancer (NSCLC) exhibits substantial heterogeneity and complexity. The landmark LAURA and POLESTAR studies have established a standard therapeutic model involving targeted consolidation therapy with osimertinib or aumolertinib after definitive chemoradiotherapy for NSCLC patients harboring EGFR-sensitive mutations. However, treatment strategies for patients with other driver gene mutations (e.g., ALK fusions, ROS1 rearrangement) still lack robust support from high-level evidence-based medical study. To enhance the standardization of diagnosis and treatment for unresectable stage III driver-positive NSCLC patients, the Radiotherapy Committee of the Chinese Society of Clinical Oncology convened an expert working group. This group identified common clinical practice issues and conducted an in-depth, problem-oriented analysis of domestic and international guidelines alongside evidence-based medical data. Through multiple rounds of comprehensive discussion and expert voting, this consensus was jointly developed. It provides evidence-based recommendations addressing frequently encountered clinical questions regarding unresectable stage III driver-positive NSCLC, aiming to serve as a key reference for clinical practice.

不可切除的III期非小细胞肺癌（NSCLC）表现出实质性的异质性和复杂性。具有里程碑意义的LAURA和POLESTAR研究已经建立了一种标准的治疗模式，包括对具有egfr敏感突变的NSCLC患者在明确的放化疗后使用奥希替尼或奥莫替尼进行靶向巩固治疗。然而，对于其他驱动基因突变（如ALK融合、ROS1重排）患者的治疗策略仍然缺乏高水平循证医学研究的有力支持。为加强对不能切除的III期驱动阳性非小细胞肺癌患者的规范化诊断和治疗，中国临床肿瘤学会放疗专业委员会召集了专家工作组。该小组确定了常见的临床实践问题，并对国内和国际指南以及循证医学数据进行了深入的、面向问题的分析。经过多轮综合讨论和专家投票，共同形成了这一共识。它提供了基于证据的建议，解决了关于不可切除的III期驱动阳性NSCLC的常见临床问题，旨在为临床实践提供关键参考。

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引用次数: 0

A TRIM21–UCHL3–ITCH–SIPA1 axis promotes colorectal cancer growth and metastasis TRIM21-UCHL3-ITCH-SIPA1轴促进结直肠癌的生长和转移。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-12-16 DOI: 10.1016/j.canlet.2025.218221

Shenghan Lou , Hao Wang , Genshen Mo , Hao Li , Haonan Xie , Yuze Huang , Huiying Li , Keru Ma , Xinyue Zhang , Meihong Yan , Jian Zhang , Yanan Pi , Peng Han

Dysregulation of protein ubiquitination and deubiquitination is a key mechanism driving tumor progression. However, the role of upstream regulators and post-translational mechanisms regulating signal-induced proliferation-associated 1 (SIPA1) stability in colorectal cancer (CRC) remains unclear. This study aimed to investigate novel deubiquitinases that directly bind to and stabilize SIPA1 based on its catalytic activity, along with their underlying action mechanisms. Notably, ubiquitin C-terminal hydrolase L3 (UCHL3) was identified as the novel deubiquitinase. Mechanistically, UCHL3 removed K48-linked polyubiquitin chains from SIPA1 at lysine 805, protecting it from proteasomal degradation. In contrast, the E3 ligase itchy E3 ubiquitin protein ligase (ITCH) promoted SIPA1 ubiquitination and degradation, acting antagonistically to UCHL3. Furthermore, UCHL3 enhanced CRC cell proliferation, invasion, and metastasis through a SIPA1-dependent mechanism. Interestingly, tripartite motif-containing protein 21 regulated UCHL3 post-translationally by targeting UCHL3 for proteasomal degradation. Clinically, UCHL3 and SIPA1 were found to be upregulated in CRC tissues, whereas ITCH was downregulated, with their expression correlating with poor patient prognosis. Altogether, the findings of this study reveal the novel UCHL3–ITCH–SIPA1 regulatory axis that modulates oncogenic signaling and CRC progression, offering new insights into the post-translational regulation of SIPA1 and identifying potential therapeutic targets.

蛋白质泛素化和去泛素化的失调是驱动肿瘤进展的关键机制。然而，上游调节因子的作用和翻译后机制调节信号诱导增殖相关1 （SIPA1）在结直肠癌（CRC）中的稳定性仍不清楚。本研究旨在研究基于SIPA1催化活性直接结合并稳定SIPA1的新型去泛素酶及其潜在的作用机制。值得注意的是，泛素c端水解酶L3 （UCHL3）被确定为新的去泛素酶。在机制上，UCHL3从SIPA1赖氨酸805处去除k48连接的多泛素链，保护其免受蛋白酶体降解。相比之下，E3连接酶瘙痒E3泛素蛋白连接酶（ITCH）促进SIPA1泛素化和降解，对UCHL3起拮抗作用。此外，UCHL3通过sipa1依赖机制增强CRC细胞的增殖、侵袭和转移。有趣的是，含有三方基序的蛋白21在翻译后通过靶向UCHL3进行蛋白酶体降解来调控UCHL3。临床发现，UCHL3和SIPA1在结直肠癌组织中表达上调，而ITCH表达下调，其表达与患者预后不良相关。总之，本研究的发现揭示了新的UCHL3-ITCH-SIPA1调控轴，该轴调节致癌信号和CRC进展，为SIPA1的翻译后调控提供了新的见解，并确定了潜在的治疗靶点。

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引用次数: 0

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