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Lymph node colonization induces tissue remodeling via immunosuppressive fibroblast-myeloid cell niches supporting metastatic tolerance.

Lymph node colonization induces tissue remodeling via immunosuppressive fibroblast-myeloid cell niches supporting metastatic tolerance. Cancer cell Haist, M., Baertsch, M. A., Reticker-Flynn, N. E., Lu, G., Kempchen, T. N., Chu, P., Vazquez, G., Chen, H., Sunwoo, J. B., Zhang, W., Laseinde, E., Adami, B., Zimmer, S., Kaufman, J., Le, Q. T., Gentles, A. J., Kong, C. S., Plevritis, S. K., Goltsev, Y., Hickey, J. W., Nolan, G. P. 2026

Abstract

Lymph node (LN) colonization in cancer is linked to poor prognosis. Evidence suggests that LN colonization induces systemic immunosuppression, facilitating distant metastasis. We investigated LN-mediated immunosuppression in patients with head-and-neck cancer using spatial proteomics, spatial transcriptomics, and an in vivo model of melanoma LN metastasis. Both primary tumors and paired LNs of nodal-positive patients exhibit enhanced interferon-? signaling and an enrichment of immunosuppressive myeloid cells and cancer-associated fibroblasts (CAFs). The spatial intersection of these myeloid-CAF-enriched niches with perifollicular T cell zones and LN follicles is linked to enhanced T cell dysfunction and Treg activation therein, thereby driving architectural LN remodeling. These immune suppressive changes extend to adjacent non-tumor-involved LN regions and nearby tumor-free LNs, but were not detected in LNs of non-cancer patients, reflecting a systemic effect that compromises anti-tumor immunity beyond the tumor-involved LN. Hence, our findings establish LN colonization as an active driver of systemic immunosuppression, facilitating metastatic progression.

View details for DOI 10.1016/j.ccell.2026.01.003

View details for PubMedID 41616773