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

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-γ 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.

• Publication year

  2026

• Venue

  Cancer Cell

• Publication date

  2026-01-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.ccell.2026.01.003PMID 41616773
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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