Thanos certainly lived up to his big bad status in Avengers: Infinity War, but Avengers 4 could see him being supplanted by a Guardian of the Galaxy.
Spoilers incoming for Avengers: Infinity War, so if you haven't seen it yet you've been warned.
With the end of Avengers: Infinity War only leaving a few heroes behind, they'll definitely need some help if they hope to take down Thanos and set things right. Unfortunately, if the movie follows the comics it is inspired by, one of their own could actually end up being the main villain.
That would be Nebula, who despite a rough start has proved to be a substantial ally to the other Guardians of the Galaxy. As we see in Infinity War though, recent times have been tough, as she was captured by Thanos and his Black Order after an assassination attempt, and has since been tortured on a daily basis. Nebula already struggled with anger and emotions thanks to her previous treatment from Thanos, and literally pulling her apart at the seams will only intensify her issues.
In the comics Nebula is tortured to an even greater degree, charring and withering her beauty and flesh and rendering her almost comatose. His hubris though allows her an opportunity to attack while he inhabits his astral form, and she is able to remove the gauntlet and put it on, making her the most powerful person in the universe.
Nebula already struggled with issues before having ultimate power, so you can imagine it is a bad idea to let her keep that power. The remaining heroes end up uniting with the Gauntlet-less Thanos to take it from her and put it into the hands of someone responsible, which in this case turns out to be Adam Warlock until he can disperse the Infinity Stones to individual owners.
Now, Nebula's characterization in the movies is a little different than in the books, as there has been a genuine arc to her character towards the heroic side. That said, she's still been through quite a lot, and her recent torture combined with the loss of Gamora could be just the thing that sends her over the edge, resulting in her being the true villain of Avengers 4.
It certainly seems Karen Gillan is down for it, so maybe it will end up happening!
Marvel Studios' Black Panther and Avengers: Infinity War are in theaters now. It will be followed by Ant-Man and the Wasp on July 6, 2018, Captain Marvel on March 8, 2019, the fourth Avengers movie on May 3, 2019, the sequel to Spider-Man: Homecoming on July 5, 2019, and Guardians of the Galaxy Vol. 3 in 2020.