Neutrophil Extracellular Trap Deposition Establishes an Immunosuppressive Environment in Non-metastatic Lymph Nodes and Facilitates Heterologous Metastatic Outgrowth

NET positivity in non-metastatic tumour-draining lymph nodes from 19 gastroesophageal adenocarcinoma patients is linked to inferior overall survival and a distinct immunoregulatory state.

• Why it matters: Tumour-draining lymph nodes are early dissemination sites yet also support adaptive immune activation, so it is unclear how they become permissive before detectable metastasis.
• What they did: Using multiplex immunofluorescence and spatial transcriptomics, the study assessed NET–Treg proximity, Treg-associated transcription, and CD8 T-cell redistribution, then tested NET effects on human T cells and tumour control in vitro.
• The result: NET-conditioned Tregs suppressed CD8 proliferation and granzyme B, and in mice NET-directed intervention (neutrophil elastase inhibition, PAD4 deficiency, or TDLN resection) attenuated increased susceptibility to a subsequent heterologous MC38 metastatic challenge.