Zhang Xiaochun, Ye Xiaorui, Jin Heiying
The Second Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing 210017, China.
The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210017, China.
Antioxidants (Basel). 2025 Jun 13;14(6):726. doi: 10.3390/antiox14060726.
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.
氧化型低密度脂蛋白（oxLDL）在微卫星稳定（MSS）和微卫星高度不稳定（MSI）的结直肠癌（CRC）中表现出差异表达，突出了其在MSS CRC中对免疫检查点抑制剂（ICI）耐药性的潜在治疗作用。MSS CRC中oxLDL水平升高通过激活如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，导致调节性T细胞（Tregs）、髓源性抑制细胞（MDSCs）和M2巨噬细胞等免疫抑制细胞的扩增，同时抑制效应T细胞功能。此外，oxLDL增强氧化应激并促进脂肪酸氧化（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耐药。本综述系统地研究了MSS和MSI CRC之间oxLDL表达的差异，并阐明了oxLDL介导ICI耐药的分子机制。此外，它还探索了针对oxLDL的潜在治疗策略，为克服MSS CRC中的免疫治疗耐药性提供了新途径。
