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In a letter to employees, Mayer said his decision to leave comes after the “political environment has sharply changed”.
His resignation comes after US President Donald Trump ordered a ban on TikTok, unless parent company Bytedance sells its US operations to an American company within 90 days.
“I have done significant reflection on what the corporate structural changes will require, and what it means for the global role I signed up for,” he said in the letter.
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Mayer, a former Disney executive, joined TikTok as CEO in May.
“We appreciate that the political dynamics of the last few months have significantly changed what the scope of Kevin”s role would be going forward, and fully respect his decision. We thank him for his time at the company and wish him well,” TikTok said in a statement.