PPP1R3G Orchestrates Tumor-Immune Crosstalk and Drives Therapeutic Vulnerability in Lung Adenocarcinoma: A Multi-Omics Exploration of Prognostic, Mechanistic, and Immunotherapeutic Insights

Background PPP1R3G, a regulatory subunit of protein phosphatase 1, remains understudied in lung adenocarcinoma (LUAD). This study systematically investigates its prognostic significance, molecular mechanisms, and therapeutic implications. Methods Multi-omics analyses integrated bulk transcriptomics (TCGA, GEO datasets), single-cell RNA sequencing, and functional assays. Prognostic modeling employed LASSO Cox regression, while pathway and tumor microenvironment (TME) dynamics were assessed via GSEA, immune deconvolution, and WGCNA. Experimental validation included qPCR, Western blot, and chemosensitivity profiling. Results PPP1R3G demonstrated marked tumor-specific upregulation (p < 0.05) and stage-dependent prognostic value. High expression correlated with advanced disease (Stage III-IV/N1-3) and poor survival (p < 0.001). Mechanistically, PPP1R3G activated cell cycle (E2F/G2M, p < 0.001) and ECM pathways while shaping an immunogenic TME with increased CD8⁺ T cells (p < 0.01) and M1 macrophages (p < 0.001). while reducing immune exclusion (p = 6.5e-06) and enhancing anti-PD-1 response (p = 0.0011). Single-cell analysis revealed PPP1R3G⁺ epithelial cells as communication hubs, regulating oxygen response, antigen presentation, and EGF/EDN signaling with alveolar macrophages. A LASSO-derived prognostic model stratified patients into distinct risk cohorts (5-year AUC = 0.675), validated in independent datasets. Functionally, PPP1R3G overexpression induced G1 arrest in malignant cells (p < 0.001) and sensitized tumors to microtubule-targeting agents ( p < 0.05). Conclusion PPP1R3G emerges as a dual-context biomarker in LUAD, driving tumor progression through cell cycle/ECM reprogramming while fostering immunotherapy-responsive microenvironments. Its prognostic model enables precise risk stratification, and chemosensitivity patterns highlight therapeutic potential. These findings position PPP1R3G as a pivotal regulator of epithelial-immune crosstalk and a promising target for combination therapies.