LAUSR

Tertiary lymphoid structures (TLS) demonstrate prognostic significance and associations with immunotherapy response in gastrointestinal malignancies, though their regulatory mechanisms remain incompletely defined. The current understanding of TLS at single-cell resolution is limited. Here, we integrated single-cell and spatial transcriptomics with TLS-specific signatures to map spatial distributions and chemokine signaling within colorectal (CRC) and gastric cancer (GC) microenvironments. We identified significant enrichment of characteristic T cell and macrophage subsets in the TLS regions. Subpopulation analyses revealed distinct cellular interaction networks: CRC exhibited robust intercellular communication among effector CD8+ T cells, exhausted CD8+ T cells, tissue-resident CD8+ T cells, CD16+ monocyte-derived macrophages, C1QC+ macrophages, and SPP1+ macrophages. Conversely, GC featured pronounced interactions between interferon-stimulated gene-positive (ISG+) CD8+ T cells and ISG15+ macrophages. Further analyses suggest CD16+ monocyte-derived macrophages may recruit effector CD8+ T cells via the CXCL16-CXCR6 ligand-receptor pair in CRC, while ISG15+ macrophages may utilize dual CXCL16-CXCR6 and CXCL10-CXCR3 pairs to recruit ISG+ effector CD8+ T cells in GC. Our study uncovers spatially resolved, cancer-type-specific immune recruitment circuits within TLS, providing mechanistic insights into their functional organization and potential therapeutic targeting.