CD97/ADGRE5 in Cancer: Structural Activation, Context-Dependent Signaling, and Therapeutic Targeting

Abstract

Highlights What are the main findings? CD97 is involved in tumor stemness, invasion, metastasis, and cell survival through adhesion-related signaling, mechanosensing, and downstream pathway activation. CD97-targeted chimeric antigen receptor (CAR) therapies have shown antitumor activity in animal models, whereas CD97-targeted antibody–drug conjugates (ADCs) are currently supported by in vitro proof-of-concept evidence and RNA-mediated downregulation remains at an early exploratory stage. What are the implications of the main findings? High CD97 expression does not necessarily mean that a tumor will respond to CD97-targeted treatment. Patient selection should consider tumor dependence on CD97, normal-tissue expression, and potential on-target/off-tumor toxicity. Abstract CD97 is an adhesion G-protein-coupled receptor encoded by ADGRE5 that integrates extracellular signals (including cell adhesion, ligand binding, and mechanical stimulation) with intracellular signal transduction. Recent structural studies have further elucidated tethered/intramolecular agonist (TIA)/Stachel recognition and engagement of the seven-transmembrane domain (7TMD), activation-associated 7TMD conformational changes, and G-protein coupling, including the structural basis for the preferential coupling of CD97 to G13. Currently, antibody–drug conjugates (ADCs) targeting CD97 are supported by in vitro proof-of-concept evidence, whereas chimeric antigen receptor (CAR) strategies have shown antitumor activity in animal models of glioblastoma (GBM) and acute myeloid leukemia (AML). Existing research indicates that CD97 is involved in maintaining stem-like states, invasion and metastasis, metabolic adaptation, and stress survival in certain tumors, and its function varies depending on tumor type and cellular environment. Because CD97 is also expressed in normal immune cells and various nonhematopoietic tissues, systemic targeted therapy may be limited by on-target/off-tumor toxicity. This article reviews the latest advances in CD97 structure and signal transduction, and explores its tumor-related functions, biomarker value, evidence for ADC and CAR-related therapies, as well as early exploratory directions involving RNA-mediated downregulation and structure-guided interventions.