Oxidized Low-Density Lipoprotein as a Potential Target for Enhancing Immune Checkpoint Inhibitor Therapy in Microsatellite-Stable Colorectal Cancer.

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Xiaochun Zhang, Xiaorui Ye, Heiying Jin
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引用次数: 0

Abstract

Oxidized low-density lipoprotein (oxLDL) exhibits differential expression in microsatellite-stable (MSS) and microsatellite instability-high (MSI) colorectal cancer (CRC), highlighting its potential therapeutic role in immune checkpoint inhibitor (ICI) resistance in MSS CRC. Elevated oxLDL levels in MSS CRC contribute to tumor progression and diminish ICI efficacy by modulating metabolic reprogramming and immunosuppressive mechanisms within the tumor microenvironment (TME) by activating receptors such as LOX-1 and CD36. oxLDL triggers signaling pathways, including NF-κB, PI3K/Akt, and MAPK, leading to the expansion of immunosuppressive cells like regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 macrophages, while concurrently suppressing effector T cell functions. Additionally, oxLDL enhances oxidative stress and promotes fatty acid oxidation (FAO) and glycolytic metabolism, resulting in nutrient competition within the TME and establishing an immunosuppressive milieu, ultimately culminating in ICI resistance. This review systematically examines the disparities in oxLDL expression between MSS and MSI CRC and elucidates the molecular mechanisms through which oxLDL mediates ICI resistance. Furthermore, it explores potential therapeutic strategies targeting oxLDL, offering novel avenues to overcome immunotherapy resistance in MSS CRC.

氧化低密度脂蛋白作为增强微卫星稳定结直肠癌免疫检查点抑制剂治疗的潜在靶点
氧化低密度脂蛋白(oxLDL)在微卫星稳定型(MSS)和微卫星不稳定型(MSI)结直肠癌(CRC)中表现出差异表达,突出了其在MSS结直肠癌免疫检查点抑制剂(ICI)耐药性中的潜在治疗作用。MSS CRC中升高的oxLDL水平通过激活LOX-1和CD36等受体,调节肿瘤微环境(TME)内的代谢重编程和免疫抑制机制,从而促进肿瘤进展并降低ICI疗效。oxLDL触发包括NF-κB、PI3K/Akt和MAPK在内的信号通路,导致免疫抑制细胞如调节性T细胞(Tregs)、髓源性抑制细胞(MDSCs)和M2巨噬细胞的扩增,同时抑制效应T细胞功能。此外,oxLDL增强氧化应激,促进脂肪酸氧化(FAO)和糖酵解代谢,导致TME内的营养竞争,并建立免疫抑制环境,最终导致ICI抗性。本文系统地研究了MSS和MSI CRC中oxLDL表达的差异,并阐明了oxLDL介导ICI抗性的分子机制。此外,它还探索了针对oxLDL的潜在治疗策略,为克服MSS CRC的免疫治疗耐药提供了新的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Antioxidants
Antioxidants Biochemistry, Genetics and Molecular Biology-Physiology
CiteScore
10.60
自引率
11.40%
发文量
2123
审稿时长
16.3 days
期刊介绍: Antioxidants (ISSN 2076-3921), provides an advanced forum for studies related to the science and technology of antioxidants. It publishes research papers, reviews and communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. Electronic files and software regarding the full details of the calculation or experimental procedure, if unable to be published in a normal way, can be deposited as supplementary electronic material.
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