Single-cell transcriptomic analysis reveals tumor-immune determinants of lymph node colonization and progression in thyroid cancer
- Anthony T. Nguyen
- Jolene Viramontes
- Isaiah Vazquez
- Catriona McWilliam
- Vaishnavi Devarakonda
- Regina Henson
- Wendy L. Sacks
- Jon Mallen-St Clair
- Yufei Chen
- Evan Walgama
- Kevin S. Scher
- Justin Moyers
- Howard M. Sandler
- Julie K. Jang
- Zachary S. Zumsteg
- Wonwoo Shon
- Stephen L. Shiao
- Allen S. Ho
2026-07-03
Lymph node (LN) metastases are a major driver of mortality across solid cancers, including thyroid carcinomas, which are known for high rates of nodal colonization. To elucidate the determinants of nodal spread, we isolated tumor-infiltrating leukocytes from primary thyroid tumors and matched metastatic LNs for single-cell RNA sequencing with validation by multiplex immunohistochemistry. Comparing the microenvironmental alterations between primary tumors and their LNs, we found that thyrocytes and tumor-associated macrophages down-regulate the expression of multiple inflammatory cytokine receptors, including TNFRSF12A and CX3CR1 , upon LN colonization. LNs were associated with the induction of regulatory T cells to suppress T cell–mediated cytotoxicity compared to matched primary tumors. Notably, tumor-infiltrating lymphocytes within LNs demonstrated increased expression of activation markers, including interleukin-7 receptor ( IL7R ). High LN expression of IL7R was significantly correlated with improved outcomes and can serve as a biomarker in this heterogeneous disease. Our findings on the dynamic equilibrium within LN metastases may offer conserved mechanisms for nodal colonization across solid tumors.