Esophageal cancer is associated with a dismal prognosis. The armamentarium of approved drugs is focused on chemotherapy with modest therapeutic benefit. Recently, checkpoint inhibitory monoclonal antibody Pembrolizumab was approved. In order to identify new targets and modalities for the treatment of esophagus squamous cell carcinoma (ESCC) we searched the literature for circRNAs involved in the pathogenesis of ESCC. We identified two down-regulated and 17 up-regulated circRNAs as well as a synthetic circRNA with efficacy in preclinical in vivo systems. Down-regulated circRNAs sponge microRNAs directed against tumor suppressor genes. Up-regulated circRNAs sponge microRNAs directed against mRNAs, which encode proteins with pro-tumoral functions. We discuss issues such as reconstitution of down-regulated circRNAs and inhibition of up-regulated circRNAs with short interfering RNA (siRNA)-related entities. Also, we address druggability issues of the identified targets.Esophageal carcinoma is the seventh most common cancer worldwide with 570,000 cases annually (1). Two major histological sub-types are esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCCs arise in squamous cells that line the esophagus, whereas EACs derive from glandular cells of the esophagus (2). The ratio of incidence between ESCC and EAC depends on the geographic location with ESCC emerging as the most frequent subtype worldwide (3). Therapies such as endoscopic resection, surgery, chemo-and radio-therapy and treatment with immune-checkpoint inhibitory monoclonal antibodies (mAbs) only confer minimal survival advantages (4-7). Among the agents under development are epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor (VEGFR), hepatocyte growth factor (HGF)-tyrosine protein kinase c-MET and fibroblast growth factor receptor 2 (FGFR2) signaling inhibitors in the format of mAbs or small molecule tyrosine kinase inhibitors (4) as well as small molecule inhibitors of mechanistic target of rapamycin (mTOR), poly(ADP)ribose-polymerase 1 (PARP1) and cyclindependent kinases (CDKs) (8-10), most of them affecting rat sarcoma (RAS), rapidly accelerated firbrosarcoma (RAF), extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase(MAPK), phosphoinosite-3-kinase (PI3K), serine-threonine kinase AKT and mTOR pathways.Despite these ongoing efforts, identification of new targets and treatment modalities for ESCC is an issue of high priority. In this review, we focus on circRNAs with documented efficacy in preclinical efficacy in in vivo models for treatment of ESCC. Circular RNASeveral types of non-coding RNAs such as t-RNA, r-RNA, siRNA, lncRNA and circRNA have been described (11). CircRNAs are covalently closed circles of RNA and are products of backsplicing events in which one exon is spliced to a preceding exon (12). A unique junction is generated which allows their specific detection by molecular probes (12). At least 30000 circRNA...