Single-cell analyses reveal lymph node-tumor ecosystem remodeling during lymph node metastasis of gastric cancer.

Abstract

Gastric cancer (GC) is a highly aggressive malignancy with a strong propensity for lymph node metastasis. To characterize the metastatic ecosystem, we perform integrated single-cell transcriptomic and T cell receptor profiling of 156,871 cells from 30 primary tumors and matched sentinel lymph nodes (SLNs), spanning non-metastatic and metastatic tumors and SLNs from non-metastatic to micro- and macro-metastatic states. We identify LN-enriched progenitor exhausted T cells as a potential reservoir for tumor-infiltrating exhausted CD8+ T cells and reveal dynamic remodeling of the lymph node microenvironment by tumor-associated macrophages during disease progression. We further show that ILC3s promote a pro-metastatic microenvironment in micro-metastatic lymph nodes through the AREG-EGFR axis, facilitating lymphatic dissemination and subsequent establishment of CD24+ tumor cells. Collectively, these findings provide a stage-resolved view of the tumor-lymph node metastatic ecosystem and identify potential therapeutic targets in GC.