There could be antagonists from Ruby's original story who see Naruto's presence as a threat and try to eliminate him and Ruby. For example, if there are any evil organizations in Ruby's world, they might target the two because of the potential power that Naruto could bring to Ruby. Another possibility is that some of Naruto's old foes might team up with local villains in Ruby's world to cause chaos.
It could be anyone really. It might be some of the traditional Naruto villains who find a way to cross over into Ruby's world. Or perhaps it could be new villains created specifically for this fanfiction that are a threat to both Naruto and Ruby.
It could be Salem's forces. Since Ruby is now a Maiden, Salem would likely want to either turn her to her side or eliminate her to prevent her from being a threat to her plans.
The White Fang could be antagonists, seeing Ruby as a symbol of human - made abominations (in their view) with her cyborg body. They might target her to make a statement against humans.
A new group of Grimm hybrids created by Salem could be the main antagonists. These hybrids could be specifically designed to hunt down the wolf pack. They would have the intelligence of humans (from Salem's influence) and the ferocity of Grimm. The wolf pack, led by Ruby, would have to figure out the weaknesses of these new enemies and fight to protect themselves and the people of Remnant.
Well, the main antagonists could be a group of rogue ninja who are hired by a powerful nation to take down Naruto. Since he is unkillable, they would have to use more underhanded tactics like trying to isolate him from his friends and allies. Or perhaps there is a dark force that is awakened by Naruto's unkillable state, thinking that he is a threat to the balance of the ninja world. This dark force could then become the main antagonist, trying to destroy Naruto at all costs.
It could be Salem. Since she is often an antagonist in the RWBY universe. She might oppose Ozpin's attempts to be with Ruby because it could disrupt her plans or she simply wants to cause chaos and pain.
It might also be some of the existing characters who have turned evil. For example, Sasuke could be corrupted by a dark power and become an antagonist again. His newfound dark powers could rival Naruto's, leading to some epic battles between the two former friends.
Well, it could have a huge impact. Naruto being Ruby's uncle might mean he imparts his ninja skills and values to her. Maybe he trains her in the ways of combat and stealth, which would change the way Ruby approaches challenges in the story.
It could be a new group of rogue ninjas who oppose the ideals of the Hidden Leaf Village. They might target Kakashi's daughter because of her connection to Kakashi and Naruto, seeing her as a symbol of the village's new generation of strength.
Maybe there are powerful dark sorcerers. These sorcerers could be trying to capture Naruto for their own evil purposes, like using his power to open a portal to a dark dimension or something, and Kurama has to protect him from them.
Another type of antagonist could be a strict professor who doesn't like Naruto's carefree attitude and Hinata's association with him. The professor might try to give them a hard time, like assigning them extra difficult projects or being overly critical in class, which becomes an obstacle in their college life and relationship.