CCL20 identified as key regulator recruiting Tregs in lung adenocarcinoma, showing prognostic and therapeutic potential.

The immunosuppressive tumor microenvironment (TME) is a critical barrier in treating lung adenocarcinoma (LUAD), limiting the efficacy of current immunotherapies. Understanding the molecular mechanisms driving this immunosuppression is crucial for developing more effective treatments. Specifically, the interplay between malignant cells and immune cells within the TME, particularly the recruitment of regulatory T cells (Tregs), represents a significant gap in current therapeutic strategies for LUAD progression.

This study employed a multi-faceted approach, integrating single-cell RNA sequencing, spatial transcriptomics, and multi-omics analysis with ensemble machine learning. Researchers then validated computational findings through in vitro and in vivo functional experiments. In vitro, they assessed the proliferative, migratory, and invasive capacities of LUAD cells after genetic ablation of CCL20. In vivo, they investigated the impact of CCL20 ablation on tumor growth in a relevant animal model. The primary endpoint was to elucidate CCL20's role in the immunosuppressive TME of LUAD and its potential as a therapeutic target.

Researchers identified a distinct, metastasis-enriched malignant epithelial subpopulation characterized by a pro-inflammatory signature and high CCL20 expression. Pseudotime and regulon analyses suggested enrichment of NF-κB/STAT signaling regulon activity during malignant evolution. Spatial transcriptomics and cellular communication inference demonstrated that CCL20-high tumor cells co-localized with and actively recruited regulatory T cells (Tregs) via the specific CCL20-CCR6 ligand-receptor pair. Multi-omics analysis confirmed that high CCL20 expression correlated with increased Treg infiltration and served as an independent prognostic biomarker. An ensemble machine learning model based on the CCL20-CCR6 axis effectively stratified high-risk patients across multiple validation datasets. Functionally, genetic ablation of CCL20 attenuated the proliferative, migratory, and invasive capacities of LUAD cells in vitro and suppressed tumor growth in vivo. > The primary causal evidence chain of this study centers on the functional validation of the CCL20-CCR6 axis in Treg chemotaxis, highlighting its critical role in LUAD immunosuppression.