胰腺癌中的多胺:重塑免疫抑制肿瘤微环境。

IF 10.1 1区 医学 Q1 ONCOLOGY
Shijuan Jiang , Bo Ren , Chen Ding , Changwei Du, Zhe Cao, Gang Yang, Hua Huang, Taiping Zhang
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引用次数: 0

摘要

胰腺导管腺癌(PDAC)是一种致命的恶性肿瘤,其特点是恶性侵袭性和预后差。新出现的证据表明,多胺代谢失调是胰腺导管腺癌免疫抑制的关键驱动因素,但这种代谢-免疫串扰的机制仍不明确。这篇综述总结了最近的研究结果,表明胰腺导管腺癌独特地依赖于谷氨酰胺衍生的鸟氨酸来重新合成多胺,由KRAS-MYC轴精心策划。通过免疫细胞的代谢重编程,多胺使肿瘤相关巨噬细胞向m2样表型极化,扩大髓源性抑制细胞,并损害T细胞活化。至关重要的是,多胺的免疫调节作用是来源依赖的:肿瘤来源的亚精胺促进T细胞衰竭,而饮食中的亚精胺通过脂肪酸氧化增强抗肿瘤免疫。临床前研究表明,包括生物合成抑制剂、精氨酸剥夺剂和多胺类似物在内的多胺靶向治疗是一种很有前景的逆转免疫抑制和提高检查点抑制剂效率的策略。这些证据表明,多胺代谢是胰腺导管腺癌的治疗脆弱性,为克服治疗耐药性提供了新的诊断工具和联合方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Polyamines in pancreatic cancer: reshaping the immunosuppressive tumor microenvironment
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, characterized by its aggressiveness and poor outcomes. Emerging evidence implicates dysregulated polyamine metabolism as a key driver of PDAC immunosuppression, yet the mechanisms underlying this metabolic-immune crosstalk remain poorly defined. This review summarizes recent findings demonstrating that PDAC is uniquely dependent on glutamine-derived ornithine for de novo polyamine synthesis, orchestrated by the KRAS-MYC axis. Through metabolic reprogramming of immune cells, polyamines polarize tumor-associated macrophages toward M2-like phenotypes, expand myeloid-derived suppressor cells, and impair T cell activation. Crucially, the immunomodulatory effects of polyamines are source-dependent: tumor-derived spermidine promotes T cell exhaustion, whereas dietary spermidine enhances antitumor immunity through fatty acid oxidation. Preclinical studies have highlighted that polyamine-targeted therapy, including biosynthesis inhibitors, arginine deprivation agents and polyamine analogue, is a promising strategy to reverse immunosuppression and enhance the efficacy of checkpoint inhibitors. These evidences establish polyamine metabolism as a therapeutic vulnerability in PDAC, offering novel diagnostic tools and combination regimens to overcome therapeutic resistance.
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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
期刊介绍: Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.
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