Multimodal spatial profiling reveals distinct myeloid-defined ENKTL subgroups and tumor-myeloid cooperativity within prognostic inflammatory niche [ENKTL_CosMx6x]

Here, we integrate spatial transcriptomic and proteomic profiling with single-cell spatial molecular imaging of ENKTL samples and identify two subgroups defined by distinct macrophage programs.

Subgroup 1 is enriched for inflammatory macrophages exhibiting IFN-α/γ responses and immune-regulatory molecules including IDO1 and CD274, whereas Subgroup 2 is immune-quiescent and macrophage-sparse, with its macrophage compartment skewed towards STAB1 macrophages with scavenging features. Notably, an NF-κB-activated and EBV-associated tumor subset is specifically enriched in Subgroup 1, displaying concurrent immunostimulatory and immunoregulatory features that parallel the co-enriched myeloid states and showing reproducible sample-level associations with these myeloid states across datasets.