Resolving the spatial and cellular architecture of intra-tumor heterogeneity by multi-region dissection of lung adenocarcinoma.

Abstract

Although the spatial characteristics within the tumor microenvironment (TME) of lung adenocarcinoma (LUAD) have been identified, the mechanisms by which these factors promote LUAD progression and immune evasion remain unclear. Using spatial transcriptomics (ST) and single-cell RNA-sequencing (scRNA-seq) data from multi-regional LUAD biopsies, consisting of tumor core, tumor edge and normal area, we sought to delineate the spatial heterogeneity and driving factors of cell co-localization. Two cancer cell sub-clusters (Cancer_c1 and Cancer_c2), associated with LUAD initiation and metastasis respectively, exhibit distinct spatial distributions and immune cell colocalizations. In particular, Cancer_c1, enriched within the tumor core, could directly interact with B cells or indirectly recruit B cells through macrophages. Conversely, Cancer_c2 enriched within the tumor edge exhibits co-localization with CD8⁺ T cells. Collectively, our work elucidates the spatial distribution of cancer cell subtypes and their interaction with immune cells in the core and edge of LUAD, providing insights for developing therapeutic strategies for cancer intervention.