免疫肿瘤学中的乳酸代谢检查点:机制和治疗意义

IF 10.1 1区 医学 Q1 ONCOLOGY
Zhe Wang, Ziyan Gu, Wendi Mo, Haijun Zhang
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引用次数: 0

摘要

免疫肿瘤学已经改变了癌症治疗方法,但其临床疗效仍然受到免疫抑制肿瘤微环境(TME)的限制。乳酸曾经被认为仅仅是糖酵解的代谢副产物,现在被认为是通过直接代谢作用及其衍生物修饰,组蛋白赖氨酸乳酸化(Kla),作为免疫TME的关键调节剂。在TME中,乳酸和Kla重编程信号通路,损害免疫功能,从而促进肿瘤免疫逃逸。这篇综述综合了乳酸代谢和组蛋白Kla作为TME中关键的免疫抑制调节剂的新证据。肿瘤来源的乳酸通过Warburg效应产生,通过两种相互关联的机制使TME酸化并破坏免疫细胞功能:直接代谢干扰和通过Kla的表观遗传重编程。组蛋白Kla代表了一种新的翻译后修饰,可驱动免疫细胞中的免疫抑制信号,作为多种癌症的预后生物标志物。此外,我们强调针对乳酸代谢的治疗策略,这在克服当前免疫治疗的局限性和提高其临床疗效方面显示出相当大的希望。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Lactate metabolic checkpoint in immuno-oncology: mechanisms and therapeutic implications
Immuno-Oncology has transformed cancer therapeutics, yet its clinical efficacy remains limited by the immunosuppressive tumor microenvironment (TME). Once considered merely a metabolic byproduct of glycolysis, lactate is now recognized as a critical regulator of immune TME through both direct metabolic effects and its derivative modification, histone lysine lactylation (Kla). Within the TME, lactate and Kla reprogram signaling pathways that impair immune function, thereby facilitating tumor immune escape. This review synthesizes emerging evidence positioning lactate metabolism and histone Kla as pivotal immunosuppressive modulators within the TME. Tumor-derived lactate, produced through the Warburg effect, acidifies the TME and disrupts immune cell function via two interconnected mechanisms: direct metabolic interference and epigenetic reprogramming via Kla. Histone Kla represents a novel post-translational modification that drives immunosuppressive signaling in immune cells, serving as a prognostic biomarker across multiple cancers. Moreover, we highlight therapeutic strategies targeting lactate metabolism, which show considerable promise in overcoming the current limitations of immunotherapy and enhancing its clinical efficacy.
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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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