A combination of Green Goblin and a chaos - causing creature from Equestria. The Green Goblin could team up with this creature and use his glider and bombs along with the creature's ability to spread chaos. They would target both Spider - Man's city and Twilight Sparkle's home, causing destruction and trying to assert their control.
Green Goblin could also work well. He could be jealous of all the attention Spiderman is getting at the homecoming and decides to crash the party. His maniacal nature would contrast well with Deadpool's zany humor and Spiderman's more responsible heroism.
It could be Doctor Octopus. He might team up with some evil spy organization. His mechanical arms and scientific knowledge combined with the sneaky tactics of the spies would make for a formidable foe for Spiderman and the Totally Spies.
The Kingpin could be a great antagonist. He could be trying to take over more of the city and sees Spiderman and Tigra as threats to his plans. He uses his criminal network and his physical strength to try and stop them.
One possible plot could be that Spider - Man gets transported to Equestria. Twilight Sparkle discovers him and is initially cautious but then realizes he has good intentions. They team up to fight a new threat that is causing chaos in Equestria, perhaps a villain who has the power to manipulate magic and technology in a dangerous way.
A new character could be created specifically for this fanfic. A mad scientist who is obsessed with cross - species experiments. He sees Rachnera as a perfect specimen and wants to use her to create an army of hybrid creatures. He would target both Rachnera and Spiderman as they try to stop his evil plans.
The symbiote could be the main antagonist. It could be a new and more powerful version that can infect mutants as well as non - mutants. It targets Female Wolverine first, trying to use her mutant healing factor to enhance itself further. Spider - Man gets involved when he realizes the symbiote is causing chaos in the city. The symbiote's ability to take over its host and gain their powers would pose a significant challenge for our heroes.
The Green Goblin could be a great main antagonist. He could be jealous of the new team - up between Spiderman and Agent Venom and see them as a threat to his own plans for the city. So he devises a series of traps and attacks to try and take them down.
The Green Goblin could also fit well. He could form an alliance with some of Wonder Woman's foes. His chaotic nature and love for destruction would contrast with the heroes' quest for peace. He could target both of them, trying to break their partnership and cause mayhem in the city.
The Green Goblin could be a great antagonist. His chaotic nature and advanced weaponry would pose a serious threat to both Spider - Man and She - Venom. He could be after a new power source related to the symbiote, which would bring him into conflict with our heroes.
One idea could be that Spiderman gets transported to Equestria where he meets Twilight Sparkle. They could team up to stop a new villain that is causing chaos in both the human world and Equestria, perhaps a villain who has the power to open portals between the two worlds and is using it to steal valuable things from both. Twilight could use her magic to help Spiderman understand the new world he's in, and Spiderman could use his combat skills to protect Twilight when they are in dangerous situations.