尽管化疗+PD-1阻断已成为晚期食管鳞癌（ESCC）的标准一线治疗，但缺乏可靠的该方案的生物标志物。我们在JUPITER-06研究的486名患者的肿瘤样本上进行全外显子组测序，并开发了一个经过拷贝数变异纠正的肿瘤突变负荷，更准确地描绘了免疫原性，并预测了化疗+PD-1的功效。我们发现了其他有利的免疫原性特征（例如HLA-I/II多样性）和与化疗+PD-1功效相关的风险致癌变异（例如PIK3CA和TET2突变）。建立了一个基于食管癌基因组的免疫肿瘤学分类（EGIC）方案，其中包括了这些免疫原性特征和致癌变异。化疗+PD-1在EGIC1（免疫原性特征有利且致癌变异呈阴性）和EGIC2（免疫原性特征有利或致癌变异呈阴性）亚组中实现了显著的生存改善，但在EGIC3亚组（免疫原性特征不利且致癌变异呈阳性）中未取得显著效果。因此，EGIC可能指导未来个体化的治疗策略，并为化疗+PD-1治疗晚期ESCC患者的机制性生物标志物研究提供指导。版权所有©2023 Elsevier Inc.。

Although chemotherapy plus PD-1 blockade (chemo+anti-PD-1) has become the standard first-line therapy for advanced esophageal squamous cell carcinoma (ESCC), reliable biomarkers for this regimen are lacking. Here we perform whole-exome sequencing on tumor samples from 486 patients of the JUPITER-06 study and develop a copy number alteration-corrected tumor mutational burden that depicts immunogenicity more precisely and predicts chemo+anti-PD-1 efficacy. We identify several other favorable immunogenic features (e.g., HLA-I/II diversity) and risk oncogenic alterations (e.g., PIK3CA and TET2 mutation) associated with chemo+anti-PD-1 efficacy. An esophageal cancer genome-based immuno-oncology classification (EGIC) scheme incorporating these immunogenic features and oncogenic alterations is established. Chemo+anti-PD-1 achieves significant survival improvements in EGIC1 (immunogenic feature-favorable and oncogenic alteration-negative) and EGIC2 (either immunogenic feature-favorable or oncogenic alteration-negative) subgroups, but not the EGIC3 subgroup (immunogenic feature-unfavorable and oncogenic alteration-positive). Thus, EGIC may guide future individualized treatment strategies and inform mechanistic biomarker research for chemo+anti-PD-1 treatment in patients with advanced ESCC.Copyright © 2023 Elsevier Inc. All rights reserved.