Abstractβ‐TrCP is an E3 ubiquitin ligase that plays important roles in multiple human cancers including esophageal squamous cell carcinoma (ESCC). Analysis of ESCC patient samples reveal that only protein level but not transcript level ofβ‐TrCP associated with patient prognosis, suggesting regulators ofβ‐TrCP protein stability play an essential role in ESCC progression and may be novel targets to develop ESCC therapies. Althoughβ‐TrCP stability is known to be mediated by the ubiquitin‐proteasome system, it is unclear which enzymes play a major role to determineβ‐TrCP stability in the context of ESCC. In this study, OTUD6B is identified as a potent deubiquitinase ofβ‐TrCP that suppress ESCC progression through the OTUD6B‐β‐TrCP‐SNAIL axis. Low OTUD6B expression is associated with a poor prognosis of ESCC patients. Importantly, all‐trans retinoic acid (ATRA) is found to promote OTUD6B translation and thus suppress ESCC tumor growth and enhance the response of ESCC tumors to anti‐PD‐1 immunotherapies. These findings demonstrate that OTUD6B is a crucial deubiquitinase ofβ‐TrCP in ESCC and suggest combination of ATRA and anti‐PD‐1 immune checkpoint inhibitor may benefit a cohort of ESCC patients.