Wang Xun, Hu Yikui
Department of Gastroenterology, Wuhan Wuchang Hospital, Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430063, P.R. China.
Department of Neurology, Wuhan Wuchang Hospital, Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, Hubei 430063, P.R. China.
Oncol Lett. 2025 Apr 16;29(6):303. doi: 10.3892/ol.2025.15049. eCollection 2025 Jun.
The understanding of how gut microbiota metabolites modulate immune escape mechanisms in colorectal cancer (CRC) remains limited. In the present study, the impact of gut microbiota metabolites on the efficacy of programmed cell death protein 1 (PD-1) and programmed cell death ligand-1 (PD-L1) immunotherapy in CRC was explored, with a particular focus on the short-chain fatty acid, sodium propionate (SP), as they key metabolite. The results of the present study, determined by CCK-8 and flow cytometry, demonstrated that 10 mM SP significantly suppressed CRC cell proliferation and induced apoptosis. By contrast, 40 mM SP, but not 10 mM, markedly increased the PD-L1 mRNA and protein expression levels. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) expression, analyzed via bioinformatics using The Cancer Genoma Atlas datasets, was significantly higher in CRC tissues compared with healthy tissues. Additionally, survival analysis uncovered that elevated IGF2BP3 levels in tumor tissues were strongly associated with poor clinical outcomes. Moreover, 40 mM SP significantly induced the expression of IGF2BP3 mRNA and protein in CRC cells. The actinomycin D assay was conducted to assess mRNA stability, whereas methylated RNA immunoprecipitation coupled with quantitative polymerase chain reaction (qPCR) and RNA immunoprecipitation-qPCR were utilized to confirm the interaction between IGF2BP3 and PD-L1 mRNA. These results indicated that IGF2BP3 served as an N6-methyladenosine (m6A) reader for PD-L1, stabilizing its mRNA in an m6A-dependent manner, thereby upregulating the PD-L1 mRNA and protein expression levels. Therefore, high-dose SP may promote tumor immune escape via the IGF2BP3/PD-L1 axis in CRC. As such, high-dose SP may synergize with PD-1/PD-L1 blockade therapies to improve clinical outcomes in patients with CRC, particularly by upregulating PD-L1 expression.
目前对于肠道微生物群代谢产物如何调节结直肠癌（CRC）免疫逃逸机制的理解仍然有限。在本研究中，探讨了肠道微生物群代谢产物对CRC中程序性细胞死亡蛋白1（PD-1）和程序性细胞死亡配体1（PD-L1）免疫治疗疗效的影响，特别关注短链脂肪酸丙酸钠（SP）这一关键代谢产物。本研究通过CCK-8和流式细胞术测定的结果表明，10 mM SP显著抑制CRC细胞增殖并诱导凋亡。相比之下，40 mM SP而非10 mM SP显著提高了PD-L1 mRNA和蛋白表达水平。使用癌症基因组图谱数据集通过生物信息学分析的胰岛素样生长因子2 mRNA结合蛋白3（IGF2BP3）表达在CRC组织中显著高于健康组织。此外，生存分析发现肿瘤组织中IGF2BP3水平升高与不良临床结局密切相关。而且，40 mM SP显著诱导CRC细胞中IGF2BP3 mRNA和蛋白的表达。进行放线菌素D试验以评估mRNA稳定性，同时利用甲基化RNA免疫沉淀结合定量聚合酶链反应（qPCR）和RNA免疫沉淀-qPCR来确认IGF2BP3与PD-L1 mRNA之间的相互作用。这些结果表明IGF2BP3作为PD-L1的N6-甲基腺苷（m6A）阅读器，以m6A依赖的方式稳定其mRNA，从而上调PD-L1 mRNA和蛋白表达水平。因此，高剂量SP可能通过CRC中的IGF2BP3/PD-L1轴促进肿瘤免疫逃逸。因此，高剂量SP可能与PD-1/PD-L1阻断疗法协同作用，以改善CRC患者的临床结局，特别是通过上调PD-L1表达。
