Esophageal cancers are common globally but are difficult to treat and have a poor prognosis. Esophageal squamous cell carcinoma (ESCC) is especially dangerous and has poorly understood molecular mechanisms. A recent study took a comprehensive look at the kappa opioid receptor (KOR), a protein that has been shown to influence the progression of other cancers. First, researchers examined existing patient datasets and found that ESCC tumors had reduced KOR expression and that lower expression of KOR was correlated with reduced patient survival. In the lab, they found that reducing KOR expression in cultured ESCC cells led to increased proliferation, invasion, and metastasis. When looking for potential mechanisms, they found that down-regulation of KOR activated the PDK1-AKT signaling pathway. It also led to invasion-related changes in cells, including invadopodia formation and cytoskeletal rearrangement. Reducing expression of KOR in mice led to increased metastasis and phosphorylation of the AKT enzyme. In cell culture, inhibiting the enzyme that phosphorylates AKT (AKT kinase) reversed the effects of KOR down-regulation. These results suggest that down-regulation of KOR directly activates pro-cancer activity in ESCC and that KOR may serve as a tumor suppressor and therapeutic target warranting further research.