Tumor microenvironment distinctions between esophageal cancer subtypes explain varied immunotherapy responses

Esophageal cancer comprises two main subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Previous studies have revealed distinct genomic characteristics between these subtypes, with ESCC sharing similarities with head and neck squamous cell carcinoma (HNSCC), and EAC aligning with gastric adenocarcinoma (GAC). Additionally, recent immunotherapy clinical trials have shown a higher response rate in ESCC and HNSCC compared to EAC and GAC. However, how the tumor microenvironment contributes to these varied immunotherapy responses remains unclear. In this study, through a comparative analysis of single-cell tumor transcriptomes from 35 patients with ESCC, EAC, HNSCC, or GAC, we identified two groups with tumor microenvironment distinctions: ESCC and HNSCC versus EAC and GAC, consistent with their genomic classifications. Malignant epithelial cells displayed distinct separations based on histological origin. In the tumor immune microenvironment, we observed an enrichment of CXCL13+CD8+ T cells and CXCL9+CXCL10+ tumor-associated macrophages (TAMs) in ESCC and HNSCC, which activate cellular immunity through interferon-{gamma}. In contrast, EAC and GAC exhibited a high presence of heat-shock protein-expressing CD8+ T cells and MARCO+ TAMs. These immune signatures help explain the varied immunotherapy responses among these cancer subtypes and successfully predict immunotherapy outcomes across diverse cancer types, underscoring their clinical significance.