Perhaps Mister Sinister. He has always been interested in mutants like Wolverine and could see Deadpool as a useful pawn or a nuisance in his grand schemes. He might try to manipulate the situation to his advantage, causing Deadpool and Wolverine to join forces against him.
A new mutant with the power to control metal could be the main antagonist. This would be a big threat to Wolverine, as his skeleton is made of adamantium. Deadpool would have to use his unorthodox methods to help Wolverine defeat this foe, all while making sarcastic remarks.
Green Goblin could also work well. He could be jealous of all the attention Spiderman is getting at the homecoming and decides to crash the party. His maniacal nature would contrast well with Deadpool's zany humor and Spiderman's more responsible heroism.
The symbiote could be the main antagonist. It could be a new and more powerful version that can infect mutants as well as non - mutants. It targets Female Wolverine first, trying to use her mutant healing factor to enhance itself further. Spider - Man gets involved when he realizes the symbiote is causing chaos in the city. The symbiote's ability to take over its host and gain their powers would pose a significant challenge for our heroes.
Venom could also be a main antagonist. Imagine if he somehow got enhanced and became even more powerful. He could be causing chaos in the city, and both Spiderman and Deadpool would have to figure out a way to defeat him. Deadpool's lack of fear and Spiderman's knowledge of Venom could be key factors in their fight.
Ra's al Ghul could also be a main antagonist. He might see Deadpool as a wildcard that could disrupt his plans for Gotham and the world. Ra's al Ghul's long - term goals of achieving immortality and controlling the world would put him at odds with both Batman and Deadpool. Deadpool's immortality might be something Ra's al Ghul wants to study or use for his own purposes, and Batman would do anything to stop Ra's al Ghul's evil schemes.
Sabretooth could be a great villain. He has a long - standing feud with Wolverine, and adding Deadpool to the mix would make things even more chaotic. His savage nature and powerful fighting skills would pose a real threat to both of them.
It could be a powerful, corrupted Pokemon trainer who wants to capture Cosmog and use its unique powers for his own evil purposes. He might see Cosmog as a key to unlocking ultimate power and doesn't care about the harm it could cause to Cosmog or the Pokemon world. He could also be in league with some dark - type Pokemon that can create obstacles for Marshadow and Cosmog.
Mr. Burns could potentially be the antagonist. He might see the combination of Spongebob and Homer as a threat to his power in Springfield. He could try to separate them and cause trouble for them. Maybe he wants to take over Bikini Bottom as well, seeing it as a new source of resources or power. He starts by spreading rumors about Spongebob and Homer in both their hometowns to turn the locals against them.
It could be Darth Sidious. Since he is always looking for power and control in the Star Wars universe, he might see Naruto as a threat to his plans when Naruto arrives in Padme's world. He would try to eliminate Naruto and use Padme as a pawn in his political games.
It could be Ra's al Ghul. He's always interested in things that can give him an edge in his quest for immortality. If he discovers the power of chakra in the Naruto world, he might try to take over both worlds. His skills as a master assassin and his vast resources would pose a huge threat to Naruto and Batman, who would have to put aside their differences to defeat him.
It could be a power - hungry ninja from within the Hidden Cloud Village who sees Raikage's relationship with Hinata as a threat to his own plans for taking over the village. He might try to spread false rumors about Hinata being a spy to turn the villagers against her and the Raikage.