GATA6: A Pan-Cancer Transcription-Factor Biomarker Linking Diagnosis, Prognosis, and Anti- Tumour Immunity

Background: GATA-binding protein 6 (GATA6) is a zinc-finger transcription factor that regulates embryonic development and cell fate. Recent studies suggest that GATA6 expression is dysregulated in multiple solid tumours, but its pan-cancer diagnostic and immunotherapeutic potential remains unexplored. Methods: Transcriptomic and proteomic data of 10 967 tumours and 727 adjacent-normal samples across 33 cancer types were retrieved from TCGA, CPTAC and GTEx portals. Differential expression, receiver-operating characteristic curves, Cox regression and Kaplan–Meier analyses were applied to evaluate the diagnostic and prognostic value of GATA6. Tumour mutational burden, microsatellite instability and immune-cell infiltration were estimated by ESTIMATE, CIBERSORT and xCell algorithms. Genetic and epigenetic alterations were interrogated via cBioPortal and GSCA. In vitro, A549 and SK-MES-1 lung cancer cells were transfected with GATA6 overexpression plasmid or siRNA; proliferation (CCK-8), apoptosis (Annexin V-FITC/PI) and colony formation were assessed. Results: GATA6 mRNA and protein levels were significantly down-regulated in 13/33 and 7/11 cancer types, respectively, but up-regulated in head-and-neck and gastric cancer (AUC ≥ 0.80, P < 0.001). Low GATA6 expression was associated with advanced stage, higher grade and shorter overall survival in kidney, thymic and uveal melanoma (HR 2.17–3.42, P < 0.05). GATA6 amplification or promoter hyper-methylation occurred in 24 tumour types and correlated with improved disease-free and progression-free survival (P < 0.01). GATA6 expression positively correlated with CD8+ T-cell, M1 macrophage and dendritic-cell infiltration, and with immune-checkpoint genes PD-L1, CTLA-4 and LAG-3 (ρ > 0.40, FDR < 0.05). Overexpression of GATA6 in lung cancer cells reduced proliferation by 48 % and increased apoptosis 2.3-fold (P < 0.01), whereas knock-down produced the opposite effect. Conclusions: GATA6 is a robust pan-cancer biomarker that links tumour suppression with favourable immune micro-environments and improved clinical outcomes. Restoring GATA6 signalling may represent a novel translational strategy to potentiate immunotherapy in lung and other solid tumours.