Pan-cancer analysis identifies adhesion G protein-coupled receptor G6 as a potential prognostic and immunotherapeutic...

Adhesion G protein-coupled receptor 6 (ADGRG6), a key seven-transmembrane receptor critical for tissue morphogenesis, has poorly defined functions across pan-cancer contexts. This study used TCGA, GTEx, GEO, and spatial transcriptomics data to comprehensively assess ADGRG6 expression patterns, clinical significance, molecular regulation mechanisms, immunomodulatory effects, and therapeutic potential across multiple cancers. In vitro analyses (BRCA/glioma cell lines) confirmed its oncogenic role; co-culture and in vivo demonstrated the immunotherapeutic potential of targeting ADGRG6. Among 33 cancer types, ADGRG6 was overexpressed in 14 (42.4 %), mainly with heterozygous deletions (78.6 %) and amplifications (21.4 %). It exhibited strong diagnostic value in 22 cancers (66.67 %, all ROC AUCs >0.7), with its high expression correlating with poor prognosis in 13 types-serving as an independent prognostic risk factor for BRCA (HR: 1.552, 95 % CI: 1.078-2.235), LGG (HR: 1.467, 95 % CI: 1.028-2.094), LUSC (HR: 1.332, 95 % CI: 1.006-1.762), and PAAD (HR: 3.169, 95 % CI: 1.557-6.451). In vitro, ADGRG6 knockdown suppressed proliferation, migration, and induced apoptosis in BRCA and glioma cells via NF-κB pathway inhibition. Spatial transcriptomics highlighted high ADGRG6 expression in malignant cell microdomains and low expression in CD8+ T cell microregions. Co-culture assays demonstrated that ADGRG6 knockdown enhanced CD8+ T cell migration and cytotoxicity. In vivo, combining ADGRG6 targeting with anti-PD-1 improved BRCA's response to immunotherapy. In three cohorts, ADGRG6 predicted favorable anti-PD-1 responses (AUC: 0.601-0.814). This study establishes ADGRG6 as a cancer-type-specific oncogene and independent prognostic marker for BRCA/LGG, proposing its targeting combined with immunotherapy as a novel approach to enhance cancer treatment efficacy.