The main antagonist could be one of the powerful and malevolent entities from 'The Suffering'. For example, the big bad demon or the tortured soul that has been corrupted by the darkness of that world and now wants to spread it to Danny's world.
Another option for the main antagonist could be a scientist from Danny's world who gets corrupted by the power and knowledge of 'The Suffering'. He could start experimenting with the dark forces from that world, thinking he can control them, but instead becomes a puppet of the evil within. He then turns against Danny, seeing him as an obstacle to his new - found power and his plans to reshape both worlds according to his own twisted vision.
Perhaps an organization made up of both Pokemon world villains and some of Danny's foes. They could be working together to create a portal that would merge the two worlds in a way that benefits them. They would be the main antagonists as they cause all kinds of chaos, stealing both Pokemon and technology from both worlds to achieve their goals.
Maybe a human hunter from Danny Phantom's world who has somehow found his way into the Ice Age. He has advanced weapons and a cruel nature. He starts hunting the Ice Age animals for sport and also wants to capture Danny Phantom because he sees Danny as some sort of strange, valuable creature. He teams up with some of the less friendly Ice Age creatures to achieve his goals.
A group of human hunters who have decided to target Danny's ghost side could be the antagonists. They might be trying to capture Danny and use him for their own experiments. Danny, feeling violated and angry, decides to take revenge by using his ghost powers to outwit them at every turn, and expose their cruel intentions to the people of Amity Park.
A new and powerful ghost that Danny has never faced before could be the main antagonist. This ghost could have unique powers that Danny isn't prepared for, and in their first encounter, it manages to defeat and kill Danny. This would set the stage for a story of revenge or trying to bring Danny back.
In the 'danny phantom is a lion fanfiction', the main antagonist could be a group of anti - phantom scientists who capture Danny when he's in lion form. They want to study his unique physiology and use his powers for their own evil experiments. They see him as a threat to their control over the human - ghost interactions and will stop at nothing to keep him locked up and experiment on him.
A new, powerful ghost that hates the Christmas cheer could be the main antagonist. This ghost could be spreading gloom and trying to cancel Christmas in Amity Park. Danny would have to figure out the ghost's motives and stop it from ruining everyone's Christmas. For example, it might be a ghost who was once a Scrooge - like figure in life and now wants to make others as miserable as he was.
A possible main antagonist could be a human who has somehow gained the ability to control ghosts and has made a deal with some dark force from the Mystery Skulls' world. This person wants to use the chaos of a crossover between the two universes to take over both the human world and the dimension where the Mystery Skulls operate. They would be a formidable foe as they can use both ghostly minions and the knowledge of the dark secrets from the Mystery Skulls' side.
His friends like Sam and Tucker are likely to be main characters too. They usually support Danny in his adventures and add a human element to the story. Sam with her gothic style and strong will, and Tucker with his tech - savvy skills are important parts of Danny's world.
It could be Sam and Tucker. Since Danny has become a villain, his former friends would likely try to stop him. They would be the main antagonists from Danny's point of view now. They would use their knowledge of Danny and their own skills to try and bring him back to the good side.
The Guys in White could be the main antagonists. If Danny becomes evil, they might see this as their chance to finally capture and experiment on him. They would be constantly chasing him, which would make Danny see them as the main obstacle in his new evil plans, and thus they would be the antagonists in the story.