DLX2 marks an immunosuppressive dendritic-cell program that reshapes cytotoxic immunity and marks a tolerogenic microenvironment in lung adenocarcinoma.

[BACKGROUND] The neuroactive ligand–receptor signaling pathway is increasingly recognized as a regulator of tumor–immune interactions, yet its contribution to lung adenocarcinoma (LUAD) progression and immune evasion remains poorly defined.

[METHODS] We integrated multi‑cohort transcriptomic datasets, including TCGA‑LUAD, GTEx lung tissues, pan‑cancer resources, single‑cell RNA‑seq spanning LUAD progression stages, dendritic‑cell subtype analyses, pySCENIC regulon inference, ligand–receptor interaction modeling, and Visium spatial transcriptomics. Neuroactive ligand–associated genes were evaluated for tumor upregulation, prognostic relevance, pathway activity, immune‑cell associations, transcriptional identity, cell–cell communication profiles, and spatial localization.

[RESULTS] DLX2 emerged as the top neuroactive‑associated candidate, showing robust tumor‑specific upregulation and strong association with poor overall, progression‑free, disease‑specific, and disease‑free survival in LUAD, with consistent adverse effects across multiple cancer types. DLX2 expression correlated with activation of cell‑cycle, chromatin‑remodeling and metabolic pathways, accompanied by a pronounced shift toward an immunosuppressive microenvironment characterized by enrichment of Tregs, exhausted T cells, and M2 macrophages and depletion of cytotoxic CD8⁺ and NK cells. Single‑cell profiling revealed that DLX2 is predominantly expressed in dendritic cells (DCs), where it defines a tolerogenic and hyper‑activated DC state marked by NF‑κB/TNF‑driven exhaustion signatures and regulon activity dominated by ATF3, FOSL2, FOSB, and ZMIZ1. DLX2 DCs exhibited enhanced communication with Tregs and exhausted T cells through inhibitory ligand–receptor networks including CTLA4–CD80/CD86, PD‑1–PD‑L1, LGALS9–HAVCR2, and TGF‑β pathways, while reducing interactions with effector lymphocytes. Spatial transcriptomics further demonstrated that DLX2 DCs are preferentially located within hypoxic, TGF‑β–rich niches co‑occupied by Tregs and Tex populations, indicating that DLX2 DCs serve as spatial and functional hubs of immune suppression.

[CONCLUSIONS] This study identifies DLX2 as a potential neuroimmune‑associated driver of dendritic‑cell–mediated immune tolerance in LUAD. DLX2 defines a dysfunctional DC phenotype that promotes T‑cell exhaustion, macrophage polarization, and the formation of immunosuppressive tumor niches. These findings reveal a mechanistic link between neuroactive ligand signaling and immune evasion and highlight DLX2 as a promising biomarker and potential therapeutic target for reprogramming antitumor immunity in LUAD.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s12672-026-04692-z.