Madara Uchiha could also be the main antagonist. Imagine if in the new game plus, he has even more enhanced Sharingan abilities. He decides to start the Fourth Great Ninja War all over again, but this time with even more devious plans. Naruto and his friends would have to find new ways to stop him, especially since he's already learned from his previous defeats.
It could be an older and more powerful version of Orochimaru. In the new game plus scenario, he might have found a way to cheat death completely and has amassed an even greater army of experimental ninjas. He could be the main antagonist as he tries to take over the ninja world with his new - found powers and knowledge.
A new character could be introduced as the main antagonist. This character could be a rogue ninja who has discovered a dark and ancient jutsu in the new game plus world. This jutsu gives him the power to control the minds of other ninjas. He sets his sights on ruling the ninja world by using this power to turn Naruto's friends against him, making him a formidable foe for Naruto to face.
It could be Orochimaru. In this fanfic, he could be a player of the same 'life - game' as Naruto, but with a much more sinister goal. He might be trying to manipulate the game rules to his advantage, like finding a way to make all the ninja in Konoha his puppets. Naruto would then have to figure out how to stop Orochimaru's evil plans within the game - like mechanics of his world.
A powerful rogue ninja who has mastered a forbidden jutsu that gives him the ability to control minds could be a great main antagonist. He could use this power to turn Naruto's friends against him, creating a lot of internal conflict within the group.
The Joker could be a great antagonist. His chaotic and unpredictable nature would contrast with Naruto's more straightforward sense of justice.
Typically, the main characters would be the ones from the original Homestuck. So, John Egbert would likely be one of the main characters. He's known for his adventure - seeking nature. Jade Harley might also be a main character, with her unique abilities and her connection to the game's mechanics. Dave Strider, with his cool - guy attitude and his role as a time - traveler of sorts, would probably be a central figure as well.
The Organization in the Claymore world could be the main antagonist. They already have a lot of secrets and do some morally ambiguous things. If Naruto shows up and starts changing the status quo, like teaching Claymore warriors to be more independent, the Organization might see him as a threat and try to eliminate him.
It could be a rogue ninja who was once a student of Orochimaru and has now developed his own dangerous jutsu. He wants to take over the ninja world and believes the old ways are holding everyone back.
Orochimaru could be a great antagonist. He might want to use Shenron's power for his own dark experiments. He could try to steal the dragon balls and manipulate the wishes to gain immortality or create an army of powerful, immortal ninja.
It could be someone who opposes Naruto's newfound admiration for Ganondorf. Maybe a traditionalist ninja who thinks Naruto is straying from the true ninja path by getting influenced by Ganondorf.
Lex Luthor could be a great antagonist. He's always looking for power and knowledge. If he discovers Naruto's abilities, he might try to use them for his own gain or see Naruto as a threat to his plans in Smallville.
It could be Orochimaru. He's always been interested in unique powers and abilities. The idea of X - 23's mutant abilities and Naruto's jinchuriki powers would be very appealing to him. He might try to capture them both to use in his experiments to gain ultimate power.