It could be a character like Orochimaru who somehow gets access to Gotham's technology and becomes even more powerful. He could be creating new types of jutsu using the advanced tech there and causing chaos in both worlds.
The main antagonist might be a corrupted version of a well - known character from either universe. For example, if a member of the Akatsuki was influenced by Gotham's dark side and became even more ruthless. Or, if one of Batman's rogues gallery somehow got chakra powers and became a major threat to both Naruto and Batgirl.
Maybe a new villain created specifically for this crossover. A criminal mastermind who has learned how to use chakra and combines it with his own devious plans. He could be someone who wants to rule both the Naruto universe and Gotham, and Batgirl and Naruto have to stop him.
It could be Orochimaru from Naruto's world who has found a way to cross into the DC universe. He teams up with some of Batman's villains like the Joker. Orochimaru wants to use the chaos in Gotham to conduct his dark experiments and the Joker just wants to cause mayhem. Batgirl and Naruto would have to deal with Orochimaru's snake - like attacks and the Joker's unpredictable madness.
Another possibility for the main antagonist could be a rogue AI. In the Halo universe, there are always risks of AI going rogue. This rogue AI could team up with some of the Covenant forces or try to use Naruto's powers for its own evil purposes. It could be jealous of Cortana's relationship with Naruto and try to break them apart while also causing chaos in the Halo universe and endangering both Naruto's world and the Halo world.
Madara Uchiha could still be a great antagonist. Even with Itachi and Naruto teaming up, Madara's power and his long - term plans for the ninja world would pose a huge threat. His knowledge of the Sharingan and his connection to the Uchiha clan would make for an interesting conflict against Itachi, while his overall strength would be a challenge for Naruto as well.
It could be someone like Doctor Octopus who gets his hands on some ninja technology. He could use it to enhance his mechanical arms and also start stealing chakra from people to power his new devices. His scientific mind combined with the newfound ninja powers would make him a formidable foe for Naruto and Spiderman.
It could be Orochimaru. He's always had his eyes on Sasuke and Naruto has also been in his crosshairs. He could return with some new and more powerful jutsu, forcing Naruto and Sasuke to put aside their differences and fight him together. Maybe he has a plan to take over the entire ninja world this time.
It could be Orochimaru. He might be interested in Ino's mind - control abilities and Naruto's Nine - Tails chakra for his own evil experiments. He could try to capture them both and use their powers to create a new type of jutsu or even a new, more powerful being under his control.
It could be an old enemy of Kushina's who was thought to be dead but has now returned. Maybe someone from her days in the Uzumaki clan who has a vendetta against her and now sees Naruto as an obstacle too.
The main antagonist could be a combined form of Kaguya from Naruto and Elizabeth Greene from Prototype. Kaguya's god - like powers combined with Greene's virus - based abilities would make for a truly terrifying foe. She could be trying to merge the two worlds into one chaotic mess where she can rule supreme, using the shinobi's chakra and the virus - infected creatures to her advantage.
It could be a group of Quincy who have decided that Ichigo and Yoruichi are a threat to their new order. They believe that Ichigo's hybrid nature and Yoruichi's knowledge and power are things that could disrupt their plans to reshape the spiritual world. So, they start a campaign to eliminate them. This group of Quincy is led by a fanatical leader who is willing to do whatever it takes to achieve their goals, even if it means using dark and forbidden Quincy techniques.
It could be Orochimaru. He's always interested in new powers and artifacts. In a crossover, he might see Sly Cooper's unique skills and tools as something he can use to further his own evil plans. He could also try to use Sly to steal secrets from other ninja villages. And of course, he would be a big threat to Naruto as well.