According to the BBC, the former Mirror journalist will be replaced by James Slack, Downing Street's current spokesperson.
"After careful consideration I have this evening resigned as No10 director of communications and will leave the post at the end of the year," Cain said in a statement. "I would like to thank the prime minister for his loyalty and leadership. I have no doubt that under his premiership the country will deliver on the promises made in the 2019 election campaign and build back better from the coronavirus pandemic."
Johnson thanked Cain for his "extraordinary service," noting his longtime aide "has been a true ally and friend and I am very glad that he will remain director of communications until the new year and to help restructure the operation. He will be much missed."
Johnson reportedly wanted Cain to head the prime minister's office, but the British press has extensively covered both opposition within the government to Cain's potential appointment as chief of staff, as well as Cain's own wavering commitment to remaining on Downing Street at all.
Labour leader Sir Keir Starmer told LBC Radio: "This is pathetic. I think millions of people will be waking up this morning, scratching their heads, saying what on earth is going on? We're in the middle of a pandemic, we're all worried about our health and our families, we're all worried about our jobs, and this lot are squabbling behind the door of No 10. Pull yourselves together, focus on the job in hand."