Background/Objectives: Colorectal cancer (CRC) is the second leading cause of cancer-related death in the US. The presence of deficient DNA mismatch repair and microsatellite instability (dMMR/MSI) in CRC is linked to responses to immune checkpoint inhibitors (ICIs). This study investigates the impact of metformin on the tumor microenvironment (TME) and clinical outcomes of patients with dMMR/MSI CRC treated with ICIs, aiming to better understand its potential role in enhancing ICI efficacy.Methods: Of 25,011 CRC patients in Caris database, 47 received both metformin and ICI therapy (Met-ICI group), and 475 patients received ICI therapy alone (ICI group). Samples underwent genomic or transcriptome sequencing at Caris Life Sciences. Immune cell fractions were estimated using quanTIseq. Univariate and multivariate survival analyses were conducted using the Cox proportional model.Results: The TME analysis of CRC patient samples revealed that TMB-High (≥10 mut/Mb) was more prevalent in the “ICI” group compared to the “Met-ICI” group (99.1% vs. 95.6%,p= 0.036). Mutation rates for most genes between the two groups were similar, but CIC gene mutations were more common in the “ICI” group than in the “Met-ICI” group (23.2% vs. 4.8%,p= 0.006). No significant differences were observed in the PD-L1 positivity rate or immune checkpoint gene expression (including IDO1, IFNG, TIM3, and CTLA4). M1 macrophages and neutrophils showed the highest infiltration among immune cells. However, the fractions of infiltrated immune cells were similar between the two cohorts. Univariate and multivariate analyses showed that there was no significant difference in patient survival between “ICI” and “Met-ICI” cohorts.Conclusions: In this retrospective analysis of real-world clinical outcomes, the concurrent use of metformin with ICIs in patients with dMMR/MSI CRC did not reveal an impact on clinical outcomes.
背景/目的：结直肠癌（CRC）是美国癌症相关死亡的第二大原因。CRC中DNA错配修复缺陷与微卫星不稳定性（dMMR/MSI）的存在与免疫检查点抑制剂（ICIs）的疗效相关。本研究探讨二甲双胍对接受ICI治疗的dMMR/MSI型CRC患者肿瘤微环境（TME）及临床结局的影响，旨在深入理解其在增强ICI疗效中的潜在作用。 方法：在Caris数据库的25,011例CRC患者中，47例同时接受二甲双胍与ICI治疗（Met-ICI组），475例仅接受ICI治疗（ICI组）。样本在Caris Life Sciences进行基因组或转录组测序。采用quanTIseq方法估算免疫细胞组分。使用Cox比例风险模型进行单变量与多变量生存分析。 结果：CRC患者样本的TME分析显示，与“Met-ICI”组相比，“ICI”组中肿瘤突变负荷高（TMB-H，≥10 mut/Mb）的患者比例更高（99.1% vs. 95.6%，p=0.036）。两组间大多数基因突变率相似，但CIC基因突变在“ICI”组中较“Met-ICI”组更常见（23.2% vs. 4.8%，p=0.006）。PD-L1阳性率及免疫检查点基因（包括IDO1、IFNG、TIM3和CTLA4）表达未见显著差异。M1型巨噬细胞和中性粒细胞在免疫细胞中浸润程度最高，但两组间浸润免疫细胞的组分比例相似。单变量与多变量分析均显示，“ICI”组与“Met-ICI”组患者的生存期无显著差异。 结论：在这项基于真实世界临床结局的回顾性分析中，dMMR/MSI型CRC患者联合使用二甲双胍与ICIs并未显示出对临床结局的影响。
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