Background/Objectives: Immune checkpoint inhibitors (ICIs) show durable efficacy in tumors with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), yet clinical responses remain heterogeneous. This study aimed to define immune subgroups within dMMR/MSI-H tumors and develop a reproducible transcriptomic signature predictive of ICI response.Methods: Four MSI-H-enriched cancer types (UCEC, COAD, READ, STAD) from The Cancer Genome Atlas were analyzed. Tumors were stratified by immune cell infiltration (MCP-counter immune composite score) and T-cell-inflamed gene expression profiles (GEP score). Integrating these two axes defined four immune subgroups. Differential expression, random forest feature selection, and pathway enrichment were performed to identify immune programs. A 20-gene immune signature representing the most immune-active subgroup was developed and validated across TCGA, GEO (GSE39582), and IMvigor210 cohorts.Results: Among the four subgroups, the most immune-active group showed strong activation of interferon signaling, antigen presentation, and T-cell-mediated pathways. The 20-gene signature—including CD74, STAT1, TAP1, and HLA-class genes—achieved high reproducibility (mean AUC = 0.95 ± 0.02; accuracy ≈ 89%). In the IMvigor210 cohort, this signature identified tumors with higher PD-L1 blockade response (55.6% vs. 32.8%,p= 0.034) and improved survival trends in the TMB-high subset.Conclusions: The proposed 20-gene signature quantitatively captures immune heterogeneity in dMMR/MSI-H tumors and serves as a practical, interpretable biomarker to identify true ICI responders and guide precision immunotherapy.
**背景/目的：** 免疫检查点抑制剂在错配修复缺陷或高度微卫星不稳定性肿瘤中显示出持久的疗效，但临床反应仍存在异质性。本研究旨在定义dMMR/MSI-H肿瘤内的免疫亚群，并开发一个可重复的、能预测ICI反应的转录组学特征。 **方法：** 分析了来自癌症基因组图谱的四种富含MSI-H的癌症类型。根据免疫细胞浸润和T细胞炎症基因表达谱对肿瘤进行分层。整合这两个维度定义了四个免疫亚组。通过差异表达分析、随机森林特征选择和通路富集分析来识别免疫程序。开发了一个代表最具免疫活性亚组的20基因免疫特征，并在TCGA、GEO和IMvigor210队列中进行了验证。 **结果：** 在四个亚组中，最具免疫活性的组显示出强烈的干扰素信号、抗原呈递和T细胞介导通路的激活。该20基因特征（包括CD74、STAT1、TAP1和HLA-I类基因等）具有很高的可重复性。在IMvigor210队列中，该特征识别出的肿瘤对PD-L1阻断治疗反应率更高，并且在TMB高的亚组中显示出改善的生存趋势。 **结论：** 所提出的20基因特征定量地捕捉了dMMR/MSI-H肿瘤的免疫异质性，可作为一个实用、可解释的生物标志物，用于识别真正的ICI应答者并指导精准免疫治疗。
Finding the True Responders: Stratifying dMMR/MSI-H Tumors for ICI Response
肿瘤(癌症)患者之家