Prognostic, chemotherapy and immunotherapy roles of GPR37/GPR37L1 in pan-cancer

G protein-coupled receptor 37 (GPR37) and G protein-coupled receptor 37 like 1 (GPR37L1) are implicated in tumorigenesis; however, their prognostic significance and roles in chemotherapy and immunotherapy responses across diverse cancers is incompletely defined. Utilizing transcriptomic, genomic, pharmacogenomic, and clinical data, we mapped the molecular landscapes of GPR37 and GPR37L1 and assessed their potential clinical value in retrospective real-world cohorts. Our analysis revealed high genetic alteration rates for GPR37 (10.2%) and GPR37L1 (10.7%). Aberrant expression of GPR37 served as a predictive biomarker for survival outcomes in breast invasive carcinoma, lower grade gliomas, and lung adenocarcinoma, a pattern similarly observed for GPR37L1. Intriguingly, the 2 receptors exhibited divergent prognostic effects in adrenocortical carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, uterine corpus endometrial carcinoma, and uveal melanoma. Evaluation of chemotherapy response identified significant correlations between the expression levels of both GPR37 and GPR37L1 and sensitivity to 21 common chemotherapeutic agents. For example, in lung adenocarcinoma, the elevated expression of either receptor was significantly associated with reduced sensitivity to cisplatin and gemcitabine. Analysis of 2 immunotherapy-treated melanoma cohorts demonstrated that high GPR37 or GPR37L1 expression correlated with inferior overall survival, a finding corroborated by immune infiltration and chemokine profiles. Our in vitro experiments demonstrated that the proposed ligand TX14A was unable to activate GPR37 and GPR37L1 through the cyclic adenosine monophosphate or extracellular signal-regulated kinase/mitogen-activated protein kinase pathways. Notably, this is the first systematic pan-cancer profiling of both GPR37 and GPR37L1 that integrates analyses of chemotherapy sensitivity, immunotherapy response, and immune landscapes. GPR37 and GPR37L1 may represent candidate biomarkers for prognostic stratification and for predicting chemotherapy and immunotherapy response.