Deciphering Tumor Microenvironment Dynamics in Tumorigenesis and Lymph Node Metastasis of Esophageal Squamous Cell Carcinoma using Single-cell RNA Sequencing

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Abstract Esophageal squamous cell carcinoma (ESCC) exhibits profound inter-tissue heterogeneity, yet how immune and stromal ecosystems diverge between primary tumors and metastatic lymph nodes remains poorly understood. Here, we generated a single-cell atlas of 344,790 cells and paired T cell receptor profiles from primary tumor mucosa, adjacent mucosa, non-metastatic lymph nodes, and metastatic lymph nodes from 18 patients with treatment-naive ESCC. We identify compartment-specific immune and stromal architectures that shape distinct antitumor responses and suppressive programs. Primary tumors were characterized by marked enrichment of regulatory T cells (T REG ) and activated dendritic cells coordinated through CTLA4-associated circuits, accompanied by accelerated CD8 + T cell differentiation toward intermediate and terminal exhaustion with loss of cytotoxicity. In contrast, metastatic lymph nodes preserved substantial pools of pre-exhausted CD8 + T cells with retained effector potential and strong clonal connectivity to the primary tumor, suggesting sustained antigen-driven trafficking. However, these reinvigoration-competent populations were embedded within a niche dominated by TREM2 high macrophages that delivered SPP1-dependent suppressive signals to exhausted and regulatory T cells. Stromal lineages also displayed niche-specific specialization: tumor mucosa contained chemokine-rich inflammatory fibroblasts, whereas metastatic lymph nodes upregulated extracellular matrix remodeling programs. Together, our findings demonstrate that ESCC progression is governed by anatomically distinct exhaustion trajectories, clonal behaviors, stromal states, and suppressive circuits. This framework provides mechanistic insight into why lymph node response is a key determinant of clinical outcome and highlights the need for site-tailored immunomodulation strategies that target T REG -mediated suppression in primary tumors and TREM2 high macrophage programs in metastatic nodes.

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