Seminars in oncology最新文献_第3页

Ubiquitin-specific proteases in pancreatic cancer: Molecular regulators of tumor progression and therapy resistance 胰腺癌中泛素特异性蛋白酶：肿瘤进展和治疗耐药性的分子调节因子。

IF 2.5 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-09-16 DOI: 10.1016/j.seminoncol.2025.152410

Jitendra Gupta , Furqan N. Al-Khateeb , Ahmad Zwenal , Ali G. Alkhathami , Malathi H , Mayank Kundlas , Laxmidhar Maharana , Ashish Singh Chauhan , Yasser Fakri Mustafa , Mohammed Jawad Alnajar

Pancreatic cancer is caused by a complicated set of molecular changes that include genetic mutations and aberrant signaling pathways, which result in tumor growth, metastatic spread, and resistance to therapeutics. Of the various molecular changes, standard modifying processes, such as ubiquitination and deubiquitination, influence protein levels, cellular localization, and protein function. In this context, ubiquitin-specific proteases (USPs), a primary class of deubiquitinases (DUBs), play a crucial role in regulating the ubiquitin-proteasome system, which controls protein degradation and activity in cells. These USPs can cause the removal of ubiquitin from target proteins, thereby reversing the ubiquitination process. They are key for maintaining cellular homeostasis by regulating the turnover of proteins, including those responsible for signal transduction, cellular processes (such as the cell cycle), and the response to stress events. At the same time, USPs (including USP21, USP13, USP51, and USP22) also affect multiple signaling pathways, including the Wnt, NF-κB, and TGF-β pathways, all of which are involved in the biology of pancreatic cancer. USPs will promote or inhibit cancer-associated pathways that drive proliferation, metastasis, immune evasion, and therapy resistance by stabilizing or destabilizing specific signaling molecules. This review will examine the mechanistic roles of USPs in pancreatic cancer, as well as the tumor behavior and therapeutic resistance that may result from the dysregulation of these proteins. Ultimately, by presenting an opportunity to develop targeted therapies against specific USPs, we hope to emphasize new therapeutic strategies that could positively impact the lives of patients suffering from this aggressive disease.

胰腺癌是由一系列复杂的分子变化引起的，包括基因突变和异常的信号通路，导致肿瘤生长、转移扩散和对治疗药物的耐药性。在各种分子变化中，标准的修饰过程，如泛素化和去泛素化，影响蛋白质水平、细胞定位和蛋白质功能。在这种情况下，泛素特异性蛋白酶（USPs），一类主要的去泛素酶（DUBs），在调节泛素-蛋白酶体系统中起着至关重要的作用，该系统控制细胞中蛋白质的降解和活性。这些USPs可以导致泛素从靶蛋白中去除，从而逆转泛素化过程。它们是通过调节蛋白质的周转来维持细胞稳态的关键，包括那些负责信号转导、细胞过程（如细胞周期）和对应激事件的反应的蛋白质。同时，USPs（包括USP21、USP13、USP51、USP22）还影响多种信号通路，包括Wnt、NF-κB、TGF-β通路，这些通路均参与胰腺癌的生物学过程。USPs将通过稳定或破坏特定信号分子来促进或抑制驱动增殖、转移、免疫逃避和治疗抵抗的癌症相关途径。本文将探讨USPs在胰腺癌中的机制作用，以及这些蛋白失调可能导致的肿瘤行为和治疗耐药性。最终，通过提供针对特定USPs开发靶向治疗的机会，我们希望强调新的治疗策略，这些策略可以积极影响患有这种侵袭性疾病的患者的生活。

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引用次数: 0

Metabolism at the core of melanoma: From bioenergetics to immune escape and beyond 黑色素瘤的核心代谢：从生物能量学到免疫逃逸及其他

IF 2.5 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-09-12 DOI: 10.1016/j.seminoncol.2025.152413

Chou-Yi Hsu , Yasmeen Kateb Ahmed , Shaker mohammed , Mohammad A. Alghamdi , Hasan S. AL-Ghamdi , Jaafaru Sani Mohammed , Mohammed Abed Jawad , Salim B. Alsaadi

Melanoma is a particularly aggressive type of skin cancer due to its rapid growth and capacity to metastasize. There is substantial metabolic reprogramming in melanoma that is linked to its malignant characteristics, including therapeutic resistance. This review intended to provide a detailed overview of the central metabolic pathways reprogrammed in melanoma, including the Warburg effect and the complex interactions between glycolysis and oxidative phosphorylation, which ultimately influence energy production, biosynthesis, and adaptation to the tumor microenvironment. We also discuss the molecular pathways that regulate these metabolic pathways and the effect these metabolic processes have on crucial elements of melanoma progression, including invasion, metastasis, and survival during nutrient deprivation and hypoxia. Furthermore, we discuss the importance of metabolism beyond glucose, including glutamine metabolism, changes in lipid metabolism, and alterations in one-carbon and nucleotide biosynthesis, as well as mechanisms critical for the proliferation and survival of melanoma cells. An emphasis is placed on the active metabolic crosstalk between melanoma cells and the immune system within the tumor microenvironment, where melanoma cells utilize nutrient competition and the production of immunosuppressive metabolites to alter and block the function of anti-tumor immune cells, thereby facilitating immune evasion and therapy resistance. Lastly, we critically assess developments targeting melanoma metabolism, including pharmacological inhibition of key metabolic enzymes and pathways, as well as metabolic modulation to enhance the efficacy of conventional and immunotherapies. Although promising, this area is complex and subject to contextual effects and metabolic heterogeneity, indicating that we still have a way to go in annotating robust and clinically relevant metabolic targets. We sought to consolidate current knowledge about melanoma metabolism and highlight the challenges, future directions, and complexity of a potential therapeutic vulnerability in the rapidly evolving field of cancer research.

黑色素瘤是一种特别具有侵袭性的皮肤癌，因为它的快速生长和转移能力。在黑色素瘤中有大量的代谢重编程，这与它的恶性特征有关，包括治疗耐药性。这篇综述旨在提供黑色素瘤重编程的中心代谢途径的详细概述，包括Warburg效应和糖酵解和氧化磷酸化之间的复杂相互作用，最终影响能量产生、生物合成和对肿瘤微环境的适应。我们还讨论了调节这些代谢途径的分子途径，以及这些代谢过程对黑色素瘤进展的关键因素的影响，包括营养剥夺和缺氧时的侵袭、转移和存活。此外，我们还讨论了葡萄糖以外代谢的重要性，包括谷氨酰胺代谢、脂质代谢的变化、单碳和核苷酸生物合成的改变，以及黑色素瘤细胞增殖和存活的关键机制。重点放在肿瘤微环境中黑色素瘤细胞与免疫系统之间的主动代谢串扰，黑色素瘤细胞利用营养竞争和产生免疫抑制代谢物来改变和阻断抗肿瘤免疫细胞的功能，从而促进免疫逃避和治疗抵抗。最后，我们批判性地评估了针对黑色素瘤代谢的发展，包括关键代谢酶和途径的药理抑制，以及代谢调节，以提高常规和免疫疗法的疗效。尽管前景光明，但这一领域很复杂，容易受到环境效应和代谢异质性的影响，这表明我们在注释稳健且临床相关的代谢靶点方面仍有一段路要走。我们试图巩固目前关于黑色素瘤代谢的知识，并强调在快速发展的癌症研究领域中潜在治疗脆弱性的挑战、未来方向和复杂性。

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引用次数: 0

Application of single-layer continuous duct-to-mucosa pancreaticojejunostomy in oncologic pancreaticoduodenectomy 单层连续胰-黏膜胰空肠吻合术在肿瘤胰十二指肠切除术中的应用

IF 2.5 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-09-11 DOI: 10.1016/j.seminoncol.2025.152415

Qun Chen , Fengyuan Liu , Lingtao Yan , Xumin Huang , Jishu Wei , Feng Guo , Jianmin Chen , Zipeng Lu , Junli Wu , Jie Yin , Pengfei Wu , Kuirong Jiang

Pancreaticojejunostomy is a critical step in pancreaticoduodenectomy, and its failure often results in pancreatic fistula. Clinically relevant pancreatic fistula (CRPF) can cause severe complications. This study evaluates the safety and feasibility of single-layer continuous duct-to-mucosa (SCD) pancreaticojejunostomy in preventing CRPF. We prospectively collected baseline characteristics and perioperative data from patients who underwent SCD pancreaticojejunostomy at our center between January and December 2020. A total of 156 patients were included in this study. The mean pancreaticojejunostomy time was 6.5 min, and the mean operation time was 247.6 min. CRPF occurred in 31 patients (19.9%), severe complications (Clavien-Dindo classification ≥III) occurred in 27 patients (17.3%), the mean length of hospitalization was 17.2 days, and the 90-days mortality was 0.0%. SCD pancreaticojejunostomy is an efficient and straightforward technique. It is applicable to various pancreatic conditions and demonstrates favorable clinical outcomes.

胰空肠吻合术是胰十二指肠切除术的关键步骤，其失败常导致胰瘘。临床相关胰瘘（CRPF）可引起严重的并发症。本研究评价单层连续胰空肠管粘膜吻合术预防CRPF的安全性和可行性。我们前瞻性地收集了2020年1月至12月在我们中心接受SCD胰空肠吻合术的患者的基线特征和围手术期数据。本研究共纳入156例患者。平均胰空肠吻合时间为6.5 min，平均手术时间为247.6 min。发生CRPF 31例（19.9%），严重并发症（Clavien-Dindo分级≥III） 27例（17.3%），平均住院时间17.2天，90天死亡率0.0%。SCD胰空肠吻合术是一种简单有效的技术。它适用于各种胰腺疾病，并具有良好的临床效果。

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引用次数: 0

Tumor tough, therapy smarter: Rethinking CAR-T for pancreatic cancer 肿瘤难治，治疗更聪明：重新思考CAR-T治疗胰腺癌

IF 2.5 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-09-04 DOI: 10.1016/j.seminoncol.2025.152411

Daniel A. Guirguis , Fariha Hasan , Natalie Morris , Andrew Alabd , Paula Mortada Shehata Tawfik , Kartick Pramanik , Manoj K Pandey

Chimeric antigen receptor (CAR) T-cell therapy has changed how we treat blood cancers but hasn't worked as well for solid tumors like pancreatic ductal adenocarcinoma (PDAC), mainly because these tumors are very aggressive and resistant to regular treatments. This review critically examines peer-reviewed studies to chart the evolution of immunotherapy in PDAC, emphasizing the unique barriers to effective CAR T-cell treatment and emerging strategies to overcome them. CAR T-cells that focus on tumor-related markers like mesothelin, HER2, and MUC1 have shown promise in early research models. However, clinical translation is hampered by obstacles such as a dense desmoplastic stroma that restricts T-cell infiltration, antigenic heterogeneity that promotes immune escape, and adverse effects including cytokine release syndrome. Recent innovations include dual-antigen targeting CARs (eg, CEA/MSLN), metabolic reprogramming to enhance T-cell function in nutrient-deprived tumor microenvironments, and stromal-targeting approaches such as fibroblast activation protein (FAP)-specific CARs and heparanase overexpression. Safety enhancements - such as reversible CAR inhibition using Dasatinib and GM-CSF neutralization - are also being explored to mitigate toxicity. Collectively, these advances represent promising strides toward enhancing the efficacy and safety of CAR T-cell therapy for pancreatic cancer. Ongoing research continues to identify new strategies to further refine these therapies, including the exploration of combination treatments with checkpoint inhibitors and novel immunomodulatory agents. As our understanding of the tumor microenvironment deepens, the potential for personalized approaches to CAR T-cell therapy may unlock even greater therapeutic benefits for patients.

嵌合抗原受体（CAR） t细胞疗法已经改变了我们治疗血癌的方式，但对胰腺导管腺癌（PDAC）等实体肿瘤的治疗效果并不好，主要是因为这些肿瘤具有很强的侵袭性，对常规治疗具有耐药性。本综述对同行评审的研究进行了严格的审查，以描绘PDAC免疫治疗的发展，强调了有效CAR - t细胞治疗的独特障碍和克服这些障碍的新策略。CAR - t细胞专注于肿瘤相关标志物，如间皮素、HER2和MUC1，在早期研究模型中显示出前景。然而，临床翻译受到一些障碍的阻碍，如限制t细胞浸润的致密结缔组织增生基质，促进免疫逃逸的抗原异质性，以及包括细胞因子释放综合征在内的不良反应。最近的创新包括双抗原靶向car（如CEA/MSLN），代谢重编程以增强营养缺乏的肿瘤微环境中的t细胞功能，以及基质靶向方法，如成纤维细胞活化蛋白（FAP）特异性car和肝素酶过表达。安全性增强——例如使用达沙替尼和GM-CSF中和的可逆CAR抑制——也正在探索以减轻毒性。总的来说，这些进展代表着在提高CAR - t细胞治疗胰腺癌的有效性和安全性方面取得了有希望的进展。正在进行的研究继续确定新的策略来进一步完善这些疗法，包括探索与检查点抑制剂和新型免疫调节剂的联合治疗。随着我们对肿瘤微环境理解的加深，CAR - t细胞治疗个性化方法的潜力可能会为患者带来更大的治疗益处。

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引用次数: 0

Sex-differential responses to immune checkpoint inhibitors across the disease continuum unified by tumor mutational burden 通过肿瘤突变负担统一的疾病连续体中免疫检查点抑制剂的性别差异反应

IF 2.5 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-09-03 DOI: 10.1016/j.seminoncol.2025.152414

Ming Zheng MD, PhD

While the efficacy of immune checkpoint inhibitors (ICIs) in advanced non–small-cell lung cancer (NSCLC) is well-established, sex-based differences in treatment responses remain insufficiently explored. This study examines how sex disparities impact ICI treatment outcomes in advanced-stage NSCLC, focusing on the role of tumor mutational burden (TMB) in these differences. This study analyzed data from 174 advanced-stage, chemotherapy-naïve, NSCLC patients treated with ICIs, including PD-1/PD-L1 and CTLA-4 inhibitors, to assess sex differences in treatment response and survival outcomes. Male patients with low TMB (<10 mut/Mb) had worse treatment responses compared to female patients. In contrast, no sex differences were observed in patients with high TMB, where both sexes exhibited similar therapeutic responses. These results suggest that high TMB may reduce the impact of sex on ICI efficacy, with male and female patients showing comparable outcomes. Furthermore, sex disparities in disease progression and overall survival were more evident in low-TMB patients, emphasizing the role of TMB in modulating sex-related differences in immunotherapy outcomes. This study highlights the importance of incorporating both sex and TMB into precision oncology. High TMB appears to equalize treatment responses between sexes, while low TMB may necessitate more personalized treatment strategies, particularly for male patients. Further research into the biological mechanisms underlying these differences is essential to optimize ICI therapies and enhance patient outcomes. Integrating both sex and TMB into clinical decision-making will help to develop more tailored and effective cancer immunotherapy.

虽然免疫检查点抑制剂（ICIs）在晚期非小细胞肺癌（NSCLC）中的疗效已得到证实，但基于性别的治疗反应差异仍未得到充分探讨。本研究探讨了性别差异如何影响晚期NSCLC的ICI治疗结果，重点关注肿瘤突变负担（tumor mutational burden， TMB）在这些差异中的作用。本研究分析了174例晚期（chemotherapy-naïve） NSCLC患者接受ICIs治疗的数据，包括PD-1/PD-L1和CTLA-4抑制剂，以评估治疗反应和生存结果的性别差异。低TMB （<10 mut/Mb）的男性患者治疗反应较女性患者差。相比之下，在高TMB患者中没有观察到性别差异，其中两性表现出相似的治疗反应。这些结果表明，高TMB可能会降低性别对ICI疗效的影响，男性和女性患者的结果相当。此外，在低TMB患者中，疾病进展和总生存期的性别差异更为明显，强调了TMB在调节免疫治疗结果的性别相关差异中的作用。这项研究强调了将性别和TMB纳入精确肿瘤学的重要性。高TMB似乎使两性之间的治疗反应相等，而低TMB可能需要更个性化的治疗策略，特别是对于男性患者。进一步研究这些差异背后的生物学机制对于优化ICI治疗和提高患者预后至关重要。将性别和TMB纳入临床决策将有助于开发更有针对性和更有效的癌症免疫疗法。

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引用次数: 0

Purine metabolism in tumorigenesis and its clinical implications 嘌呤代谢在肿瘤发生中的作用及其临床意义

IF 2.5 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-09-02 DOI: 10.1016/j.seminoncol.2025.152409

Zerui Lu , Jiayi Li , Ying Liu , Hui Li , Ying Sun , Rui Geng , Jiahang Song , Jinhui Liu

Metabolic reprogramming constitutes a hallmark of malignant neoplasms. Purine metabolism emerges as a pivotal regulator in cellular metabolic networks through multiple mechanisms, including dysregulation of de novo biosynthesis/salvage pathway coordination, adenosine-mediated immunosuppressive microenvironment formation, and collective contributions to tumorigenesis and malignant progression. During metastatic progression, purine metabolism reinforces tumor cell plasticity through mitochondrial energy regulation and modulation of cell cycle checkpoints (eg, G1/S transition). These mechanistic revelations have positioned purine metabolism-targeting strategies as promising oncotherapeutic candidates. This review methodically analyzes (1) purine metabolic pathways and their regulatory dynamics, (2) adenosine-mediated pathophysiological interactions, and (3) the synergistic impacts of these pathways in malignant transformation. We propose a unified mechanistic framework that clarifies oncogenic purine metabolic rewiring while evaluating translational potential through three clinical dimensions: pathogenesis elucidation, diagnostic biomarker discovery, and targeted therapeutic development. This comprehensive synthesis aims to advance precision oncology through mechanistic insights and therapeutic innovation.

代谢重编程是恶性肿瘤的一个特征。嘌呤代谢通过多种机制在细胞代谢网络中发挥关键调节作用，包括对新生生物合成/挽救途径协调的失调、腺苷介导的免疫抑制微环境的形成以及对肿瘤发生和恶性进展的共同贡献。在转移过程中，嘌呤代谢通过线粒体能量调节和细胞周期检查点（如G1/S转变）的调节来增强肿瘤细胞的可塑性。这些机制的揭示已经定位嘌呤代谢靶向策略作为有希望的肿瘤治疗候选人。本文系统分析了(1)嘌呤代谢途径及其调控动力学，(2)腺苷介导的病理生理相互作用，以及(3)这些途径在恶性转化中的协同作用。我们提出了一个统一的机制框架来阐明致癌嘌呤代谢重布线，同时通过三个临床维度评估转化潜力：发病机制阐明、诊断性生物标志物发现和靶向治疗开发。这一全面的综合旨在通过机制见解和治疗创新来推进精准肿瘤学。

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引用次数: 0

Unveiling the role of RAI14 in cancer: Biological significance and translational perspectives 揭示RAI14在癌症中的作用：生物学意义和翻译观点

IF 2.5 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-09-02 DOI: 10.1016/j.seminoncol.2025.152412

Zhi-Xiong Chong

Retinoic acid-induced protein 14 (RAI14) is an actin-binding protein that regulates actin dynamics, cell adhesion, and migration. RAI14 dysregulation has been reported to facilitate the development of at least 10 tumor types based on the findings from over 20 original research articles. This review article aims to fill in the gap in the literature by providing a comprehensive summary of the putative tumor-regulatory roles of RAI14 in different cancers. Overall, RAI14 can affect protein kinase B (AKT), mammalian target of rapamycin, yes-associated protein/Hippo, apoptosis, and epithelial-to-mesenchymal transition activities to promote tumorigenesis. Several noncoding RNAs like miR-23b-3p and AFAP1-AS1 can directly or indirectly affect RAI14 expression to control its tumor-modulatory function epigenetically. Additionally, RAI14 tissue or serum level are overexpressed in at least seven human tumors, including breast, gastrointestinal, genitourinary, and brain cancers. This gives RAI14 the translational potential as a diagnostic or prognostic biomarker. Targeting RAI14 as a cancer antigen can also potentially help halt tumor progression. Future large-scale trials are needed to confirm the tumor-regulatory role of RAI14 in human cancer and to evaluate the sensitivity, reliability, and accuracy of using this target as a biomarker or therapeutic target.

视黄酸诱导蛋白14 （Retinoic acid-induced protein 14, RAI14）是一种肌动蛋白结合蛋白，可调节肌动蛋白动力学、细胞粘附和迁移。根据20多篇原创研究文章的发现，RAI14失调已被报道促进了至少10种肿瘤类型的发展。本文旨在通过全面总结RAI14在不同癌症中可能的肿瘤调节作用来填补这一文献空白。总体而言，RAI14可以影响蛋白激酶B （AKT）、哺乳动物雷帕霉素靶点、酵母相关蛋白/Hippo、细胞凋亡和上皮间质转化活性，从而促进肿瘤发生。miR-23b-3p、AFAP1-AS1等几种非编码rna可直接或间接影响RAI14的表达，从表观遗传上控制其肿瘤调节功能。此外，RAI14在至少7种人类肿瘤中组织或血清水平过表达，包括乳腺癌、胃肠道、泌尿生殖系统和脑癌。这使得RAI14具有作为诊断或预后生物标志物的翻译潜力。靶向RAI14作为癌症抗原也可能有助于阻止肿瘤进展。未来的大规模试验需要证实RAI14在人类癌症中的肿瘤调节作用，并评估使用该靶点作为生物标志物或治疗靶点的敏感性、可靠性和准确性。

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引用次数: 0

Application prospects of tumor vaccines for pancreatic cancer: From TAAs to TSAs and combination strategies 胰腺癌肿瘤疫苗的应用前景：从TAAs到TSAs及联合策略

IF 2.5 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-08-20 DOI: 10.1016/j.seminoncol.2025.152399

Zerui Lu , Wenxin Zhu , Xinjian Liu

Pancreatic cancer, a highly aggressive malignancy of the digestive system, exhibits therapeutic resistance due to its immunosuppressive tumor microenvironment (TME) and early metastatic potential. Cancer vaccines targeting tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs) have emerged as promising immunotherapeutic strategies. TAA-based vaccines demonstrate T cell activation and tumor suppression in preclinical models, yet face limitations from antigen heterogeneity and immunosuppressive TME. TSA-directed vaccines, exemplified by personalized mRNA vaccines incorporating whole-exome sequencing-selected neoantigens, achieved long-term recurrence-free survival in 50% of vaccinated patients during phase I/II trials, with phase III data supporting synergistic efficacy when combined with chemotherapy and programmed death receptor 1 (PD-1) inhibitors. KRAS-targeted vaccines address common mutations (e.g., G12D, G12V) to broaden applicability. This review presents an updated summary of current tumor vaccine types, mechanisms, and clinical implications, while analyzing how combination therapies remodel TME infiltration and reverse T cell exhaustion to significantly improve survival outcomes. The discussion also addresses existing challenges and proposes future directions in pancreatic cancer vaccine development.

胰腺癌是一种高度侵袭性的消化系统恶性肿瘤，由于其免疫抑制肿瘤微环境（TME）和早期转移潜力而表现出治疗耐药性。针对肿瘤相关抗原（TAAs）或肿瘤特异性抗原（TSAs）的癌症疫苗已成为有前途的免疫治疗策略。基于taa的疫苗在临床前模型中显示出T细胞活化和肿瘤抑制，但面临抗原异质性和免疫抑制TME的限制。tsa导向疫苗，以结合全外显子组测序选择的新抗原的个性化mRNA疫苗为例，在I/II期试验中，50%接种疫苗的患者实现了长期无复发生存，III期数据支持与化疗和程序性死亡受体1 （PD-1）抑制剂联合使用时的协同效果。针对kras的疫苗针对常见突变（例如G12D、G12V），以扩大适用性。本文综述了当前肿瘤疫苗类型、机制和临床意义的最新总结，同时分析了联合治疗如何重塑TME浸润和逆转T细胞衰竭以显着改善生存结果。讨论还涉及现有的挑战，并提出胰腺癌疫苗开发的未来方向。

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引用次数: 0

The effects of microbiota-derived short-chain fatty acids on T lymphocytes: From autoimmune diseases to cancer 微生物源性短链脂肪酸对T淋巴细胞的影响：从自身免疫性疾病到癌症

IF 2.5 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-08-19 DOI: 10.1016/j.seminoncol.2025.152398

Mohamed J. Saadh , Omer Qutaiba B. Allela , Suhas Ballal , Morug Salih Mahdi , Mamata Chahar , Rajni Verma , Rouaida Kadhim A Al-hussein , Mohaned Adil , Mahmood Jasem Jawad , Ali M. Ali Al-Nuaimi

Short-chain fatty acids (SCFAs), acetate, propionate, and butyrate, are the microbial metabolites that have significant functions in host immune modulation, especially T lymphocyte function. Implication by recent evidence indicates SCFAs regulate T-cell growth, differentiation, metabolism, effector function, and apoptosis through histone deacetylase (HDAC) inhibition, G-protein-coupled receptor (GPCR) signaling, and metabolic reprogramming processes. Butyrate, for example, enhances regulatory T cell (Treg) and Interleukin 10 (IL-10)-producing T helper 1 (Th1) cell differentiation as well as context-dependent regulation on T helper 17 (Th17) cell development. SCFAs also impact cytotoxic CD8+ T cells through augmented production of IFN-γ and memory formation, which enhances antiviral and antitumor immunity. SCFAs reprogram T-cell metabolism through enhanced acetyl-CoA, mechanistic target of rapamycin (mTOR) signaling, and fatty acid oxidation (FAO), thus promoting the unique metabolic requirements of effector and memory T-cell subsets. In addition, SCFAs induce apoptosis of activated T cells through the Fas upregulation by inhibiting HDAC1. SCFA dysregulation plays a role in disease and autoimmune disorders like type 1 diabetes and rheumatoid arthritis, whereas therapeutic supplementation reduces inflammation and immune tolerance. SCFAs also amplify the antitumor effect of immune checkpoint inhibitors (eg, anti-programmed cell death protein 1 (anti-PD-1)) in cancer by driving CD8+ T-cell activation, infiltration, and Interferon gamma (IFNγ) production, partially through the transcriptional regulator Inhibitor of DNA binding 2 (ID2). Significantly, tissue- and disease-specific differential expression and functional implication of SCFA receptors (eg, GPR43, GPR41, GPR109A) emphasize the complexity of SCFA-mediated signaling. In conclusion, the current review emphasizes the multifunctional role of microbiota-derived SCFAs in T lymphocyte biology and their therapeutic potential in cancer, infection, and autoimmune diseases.

短链脂肪酸（SCFAs），醋酸酯、丙酸酯和丁酸酯是在宿主免疫调节，特别是T淋巴细胞功能中具有重要功能的微生物代谢物。最近的证据表明，SCFAs通过抑制组蛋白去乙酰化酶（HDAC）、g蛋白偶联受体（GPCR）信号传导和代谢重编程过程调节t细胞的生长、分化、代谢、效应功能和凋亡。例如，丁酸盐可以增强调节性T细胞（Treg）和产生白细胞介素10 （IL-10）的辅助性T细胞1 （Th1）细胞的分化，以及对辅助性T细胞17 （Th17）细胞发育的环境依赖性调节。SCFAs还通过增加IFN-γ的产生和记忆形成来影响细胞毒性CD8+ T细胞，从而增强抗病毒和抗肿瘤免疫。SCFAs通过增强乙酰辅酶a、雷帕霉素（mTOR）信号传导机制靶点和脂肪酸氧化（FAO）来重编程t细胞代谢，从而促进效应t细胞亚群和记忆t细胞亚群独特的代谢需求。此外，SCFAs通过抑制HDAC1而上调Fas，诱导活化的T细胞凋亡。SCFA失调在1型糖尿病和类风湿性关节炎等疾病和自身免疫性疾病中发挥作用，而治疗性补充可减少炎症和免疫耐受。SCFAs还通过驱动CD8+ t细胞活化、浸润和干扰素γ (IFNγ)的产生，部分通过转录调节因子DNA结合2抑制剂（ID2），增强了免疫检查点抑制剂（例如抗程序性细胞死亡蛋白1 (anti-PD-1)）在癌症中的抗肿瘤作用。值得注意的是，组织和疾病特异性的SCFA受体（如GPR43、GPR41、GPR109A）的差异表达和功能意义强调了SCFA介导的信号传导的复杂性。总之，本综述强调了微生物来源的SCFAs在T淋巴细胞生物学中的多功能作用及其在癌症、感染和自身免疫性疾病中的治疗潜力。

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引用次数: 0

Deregulated cell cycle control: The interplay between non-coding RNAs and cyclin-dependent kinases in tumorigenesis 细胞周期失控：非编码rna和周期蛋白依赖性激酶在肿瘤发生中的相互作用

IF 2.5 3区医学 Q2 ONCOLOGY

Seminars in oncology

Pub Date : 2025-08-12 DOI: 10.1016/j.seminoncol.2025.152395

Chou-Yi Hsu , Yasir Qasim Almajidi , Maher abdulrazzaq Al-hakeem , Mohammad Y. Alshahrani , Wael Nabil , Sujayaraj Samuel Jayakumar , Siya SinglaI , Zahraa Abbas Al-Khafaji , Ahmed Remthan Hussein , Zuhair I. Al-Mashhadani

Cyclin-dependent kinases (CDKs) are a group of serine/threonine kinases that are at the center of cell cycle progression. Dysregulated CDK activity, found in a range of human cancers, leads to uncontrolled cell growth and development. Non-coding RNAs (ncRNAs), which include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are emerging as critical regulators of gene expression and cellular processes, playing an important and often complex role in cancer development and progression. The purpose of this review is to organize knowledge about the interactions of ncRNAs with CDKs, contribution to cancer biology, and to discuss not only the different ways miRNAs target and downregulate CDKs mRNA, leading to inhibition of cell cycle progression and acting as tumor suppressors, but in the case of some miRNAs alter CDK activity as oncogenes by directly upregulating CDK expression or more frequently suppressing the expression of the canonical CDK inhibitors (p21 and p27). Moreover, long non-coding RNAs (lncRNAs) can regulate CDKs through a variety of mechanisms, such as functioning as molecular sponges by absorbing miRNAs that target CDK proteins as miRNA sponges, modulating CDK protein abundance and/or activity indirectly or directly (i.e., the direct interaction with the CDK proteins can potentially invoke an ability to regulate their stability, etc.). Circulating RNAs (circRNAs) also primarily modulate CDK levels and act as inhibitors of the appropriate CDK targeted by a miRNA sponge, potentially through direct interaction with a CDK. Overall, while our understanding of the ncRNA-CDK network is far from complete, the complexities surrounding ncRNA-CDK oncogenic developments and the ability to target these pathways offer significant promise in the harsh realities of cancerogenesis and further therapeutic interventions to fashion more precise cancer therapies that antagonize aberrant cell cycle progression in cancer subtypes.

细胞周期蛋白依赖性激酶（CDKs）是一组丝氨酸/苏氨酸激酶，处于细胞周期进程的中心。在一系列人类癌症中发现的CDK活性失调会导致细胞生长和发育失控。非编码rna (ncRNAs)，包括微rna （miRNAs）、长链非编码rna （lncRNAs）和环状rna (circRNAs)，正在成为基因表达和细胞过程的关键调节因子，在癌症的发生和进展中发挥着重要而复杂的作用。本综述的目的是组织有关ncRNAs与CDKs相互作用的知识，对癌症生物学的贡献，并不仅讨论miRNAs靶向和下调CDKs mRNA的不同方式，导致细胞周期进程的抑制和肿瘤抑制，而且在一些miRNAs通过直接上调CDK表达或更频繁地抑制典型CDK抑制剂的表达来改变CDK活性作为癌基因（p21和p27）。此外，长链非编码rna （lncRNAs）可以通过多种机制调节CDKs，例如通过吸收靶向CDK蛋白的miRNA作为miRNA海绵发挥分子海绵的作用，间接或直接调节CDK蛋白的丰度和/或活性（即，与CDK蛋白的直接相互作用可以潜在地调用调节其稳定性的能力等）。循环rna （circRNAs）也主要调节CDK水平，并作为miRNA海绵靶向的适当CDK的抑制剂，可能通过与CDK的直接相互作用。总的来说，虽然我们对ncRNA-CDK网络的理解还远未完成，但围绕ncRNA-CDK致癌发展的复杂性和靶向这些途径的能力为癌症发生的残酷现实和进一步的治疗干预提供了重要的希望，以形成更精确的癌症治疗方法，对抗癌症亚型中异常的细胞周期进展。

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引用次数: 0