Maybe a corrupt Shinigami officer who has always been against Ichigo. When he hears about Ichigo's transformation into a female Arrancar, he uses it as an excuse to label her as a dangerous outcast and tries to hunt her down. This officer could be power - hungry and see Ichigo as a threat to his own rise in the Soul Society.
Perhaps the story could start with Ichigo being experimented on by a rogue group of scientists or powerful Hollows. They accidentally turn him into a female Arrancar. Ichigo then has to adapt to her new physical form. She might discover new abilities that are unique to female Arrancars, like a different type of Cero or Sonido. Along the way, she could make new allies among the Arrancars who see her as an opportunity for change, and she tries to use her new position to bring peace between the warring factions.
There could be a group of corrupted Quincy who view Ichigo's resurrection as an abomination. They believe that his power goes against the natural order of things. So, they band together to try and eliminate him. They might have some new and dangerous weapons or techniques specifically designed to counter Ichigo's resurrected powers. This group could be led by a very powerful Quincy who has a personal vendetta against Ichigo or the Soul Reapers in general.
Dr. Sivana could still be the main antagonist. His hatred for Shazam wouldn't change just because Billy is now female. In fact, he might be even more enraged or intrigued by this new development and try to take advantage of it in some way.
A jealous male trainer could be the main antagonist. He might see Ash's transformation as an unfair advantage given by some mysterious power. He constantly tries to undermine her in battles and challenges, believing that a female should not be as successful as a male in the Pokemon world.
Perhaps a vampire scientist who is conducting unethical experiments on both humans and vampires. Ichigo gets in his way when he discovers what the scientist is doing. This antagonist could be using his scientific knowledge to create powerful and dangerous hybrids. He believes that he is creating a new and better vampire - human world order, but his methods are causing a lot of harm, and Ichigo is determined to stop him.
A powerful sorcerer could be the main antagonist. This sorcerer might be after the same power source that Ichigo and Jackie are either protecting or trying to use for good. The sorcerer could be using dark magic to create chaos in their world and trying to stop Ichigo and Jackie from achieving their goals.
A powerful AI that has gone rogue in the game world could be a great antagonist. It could be constantly creating new and difficult challenges for Ichigo, trying to prevent him from escaping the virtual reality.
There could be a group of anti - hybrid fanatics. They believe that the existence of a Naruto - Ichigo descendant is an abomination that goes against the natural order of both worlds. They form a secret society and start causing chaos, trying to eliminate the descendant. Their leader could be a former ninja who lost his family in a war and blames the mixing of powers for all the world's problems. They would be a complex antagonist as they have their own warped ideology to drive their actions.
Maybe a giant lemon - themed monster. This monster is created by some dark force that wants to disrupt the balance between the two worlds in the crossover. It has the ability to spit out acidic lemon juice that can corrode anything. Ichigo has to figure out its weakness and defeat it to restore peace. The monster could be controlled by an unseen force that is the real antagonist behind the scenes.
A powerful Hollow that has the ability to disrupt Ichigo's gamer powers could be the main antagonist. This Hollow might be able to hack into Ichigo's power system, so to speak, and cause glitches in his abilities, making it difficult for him to fight.