SLPI ⁺ AT2‐Like Cells Orchestrate Lung Adenocarcinoma Invasion via Wnt Pathway Activation and Stromal Crosstalk in a Spatially Defined Margin Niche

Abstract The spatial organization of the tumor microenvironment (TME) profoundly influences cancer biology. However, the cell types and spatial distribution driving lung adenocarcinoma (LUAD) invasion remain poorly understood. By integrating spatially resolved transcriptomics with scRNA‐seq data, we identify a novel secretory leukocyte protease inhibitor (SLPI)‐expressing AT2‐like subpopulation that localizes specifically at the invasive tumor margin, which drives the transition from minimally invasive (MIA) to invasive (IA) LUAD. Functional characterization reveals that SLPI ‐expressing AT2‐like cells upregulated Dickkopf‐1(DKK1), enhancing tumor cell stemness and epithelial‐mesenchymal transition (EMT). Furthermore, spatially co‐localized MRC1‐expressing resident tissue macrophages (RTM‐TAMs) secrete pro‐tumor cytokines upon interaction with SLPI + tumor cells, alongside cancer‐associated myofibroblasts (myo‐CAFs) exhibiting reduced type I collagen production. These TME components establish a pro‐tumorigenic niche and engaged in synergistic interactions with SLPI + AT2‐like cells to facilitate LUAD invasion. These findings reveal the specific cellular composition, spatial architecture, and functional crosstalk between tumor cells and TME subpopulations that orchestrated LUAD progression. The frontier molecular targets at the tumor invasive identified in this study can serve as a basis for developing novel therapeutic targets in the future and assist pathologists in accurately assessing patients' disease progression and survival outcomes.