An unexpected observation among the COVID-19 pandemic is that smokers constituted only 1.4％-18.5％ of hospitalized adults,calling for an urgent investigation to determine the role of smoking in SARS-CoV-2 infection.Here,we show that cigarette smoke extract (CSE) and carcinogen benzo(a)pyrene (BaP) increase ACE2 mRNA but trigger ACE2 protein catabolism.BaP induces an aryl hydrocarbon receptor (AhR)-dependent upregulation of the ubiquitin E3 ligase Skp2 for ACE2 ubiquitination.ACE2 in lung tissues of non-smokers is higher than in smokers,consistent with the findings that tobacco carcinogens downregulate ACE2 in mice.Tobacco carcinogens inhibit SARS-CoV-2 spike protein pseudovirions infection of the cells.Given that tobacco smoke accounts for 8 million deaths including 2.1 million cancer deaths annually and Skp2 is an oncoprotein,tobacco use should not be recommended and cessation plan should be prepared for smokers in COVID-19 pandemic.