Single‐Cell and Spatial Transcriptomic Analysis Reveals Shared and Cancer‐Type‐Specific Cellular Interactions and Chemokine Signaling Associated With Tertiary Lymphoid Structures in Colorectal and Gastric Cancers

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ABSTRACT 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.

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