Another option is a being made of pure energy from a dimension beyond the gate. It feeds on chaos and aims to bring chaos to the Naruto world by pitting all the ninja villages against each other.
Perhaps an ancient and evil ninja from a long - lost clan that was sealed away behind the gate. He resents the modern ninja world and wants to destroy it. He has unique and powerful jutsus that Naruto and his friends have never seen before.
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.
A new character could be created. This character could be a powerful slug - human hybrid who has been corrupted by the dark side of both worlds' powers. He wants to rule over both Naruto's world and Slugterra, believing that the two worlds should be united under his rule. He has the ability to use both ninja techniques and slug powers, making him a very difficult opponent to defeat.
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 a powerful dark spirit from Kagome's world that somehow manages to cross over to the Naruto universe and starts causing chaos. This spirit might be immune to normal ninja attacks and require Kagome's spiritual powers to be defeated.
Maybe another kitsune who has gone bad. In the fanfiction world, there could be a rogue kitsune who sees Naruto as a threat. This antagonist kitsune might be jealous of Naruto's power or his connection to the human world. They could try to undermine Naruto's attempts to protect the village or his friends.
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.
Madara Uchiha would also make a great antagonist. Imagine if he was resurrected and saw Naruto with Samehada as a threat to his plans of creating a new world order. He would use his Sharingan and Rinnegan powers to try and take Samehada from Naruto, believing that with it, he could easily defeat all who oppose him and reshape the ninja world according to his will.
Another possibility is a corrupted dragon spirit that has been awakened due to the mixing of the two worlds. This spirit could be spreading chaos and trying to destroy both the ninja world and the dragon world. Naruto would have to figure out a way to stop it, as it has powers that are beyond what he has faced before.
Perhaps an ancient evil that has been sealed away in the empire for centuries but is released due to the chaos of the crossover. This entity could be more powerful than any foe the Naruto characters have faced before, forcing them to find new ways to fight.