It could be Orochimaru. Since he's always interested in power and strange abilities, he might see Demon Naruto as a perfect specimen for his experiments. He would try to capture Naruto, and Shizune, being a loyal shinobi, would oppose him.
Perhaps a new group of rogue ninjas who are envious of Naruto's power. They see his demonic form as a way to gain ultimate power for themselves. So they plot against him, and Shizune gets caught in the middle as she tries to keep Naruto safe from their schemes.
The villagers themselves could be antagonists in a way. Their fear of Naruto's 'demon' side might lead them to try and ostracize or even harm him.
The main characters are obviously Naruto and Shizune. Naruto is a well - known character from the Naruto series, a hyper - energetic and powerful ninja with big dreams. Shizune is Tsunade's assistant, a skilled medical ninja.
Maybe the Hidden Leaf Village elders could turn into antagonists. They might fear Naruto's new power as the demon king and try to undermine him. They could form alliances with other villages to try and take down Naruto. Also, there could be some new, unknown powerful forces that emerge because of Naruto's transformation. These could be ancient evils that were once sealed away but are now awakened by Naruto's new demonic presence.
One possible plot could be that Demon Naruto, with his newfound demonic powers, is shunned by the village. Shizune, being a kind - hearted person, tries to understand him. She might see that beneath his demonic exterior, Naruto is still the same boy with a good heart. So she could try to help him control his powers and regain the trust of the village.
It could be a rogue ninja who has a vendetta against Shizune's family. This ninja might see Naruto as an obstacle in his path to revenge. He could target Naruto to get to Shizune and try to break their family - like bond.
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.
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.
Anko might not be a traditional antagonist, but if she is siding with Evil Naruto for some reason, she could be seen as an antagonist from the perspective of the other villagers. However, it's also possible that she is being manipulated herself, in which case the true antagonists would be those doing the manipulating.
It could be some rogue ninjas who are against Naruto's new peaceful policies as Hokage. They might see Hinata as a weakness to be exploited to get to Naruto.