Jagged1+ Tregs mediate lymphatic remodeling in tumor-draining lymph nodes.

Tumor-draining lymph nodes (tdLNs) undergo extensive stromal remodeling during tumor progression, but the immune signals that shape this process remain unclear. Here, using the B16-F10 melanoma model, we examine the role of Jagged1-expressing regulatory T cells (Jag1+ Tregs) in tdLN remodeling. Jag1 expression is increased in late-stage versus early-stage tdLN Tregs. Conditional deletion of Jag1 in Tregs (Foxp3ΔJag1) attenuates tdLN expansion without altering effector T cell abundance or activation. Bulk transcriptomic analysis identifies stromal-related transcriptional changes in Foxp3ΔJag1 tdLNs, including altered expression of genes linked to lymphatic endothelial cell (LEC) biology. Consistent with this, flow cytometry and histological analysis show reduced tdLN lymphatic expansion, while fluorescein isothiocyanate (FITC)-dextran tracing indicates altered lymphatic drainage. Jag1+ Tregs are also detected in tdLNs in patients with melanoma. Together, these findings identify Jag1+ Tregs as regulators of the tdLN lymphatic microenvironment during melanoma progression.