I'm voting for Spider-Man: Web of Shadows 2. Hopefully with Josh Keaton or Christopher Daniel Barnes voicing Spider-Man (or both, read on). I'm thinking a symbiote invasion. Picking up where the last game left off, the Venom symbiote has been locked up by Nick Fury and kept in the custody of SHIELD. A few years later, it starts emitting a noise that gets SHIELD's attention, and they realize it's a warning that the race of Symbiotes that had initially locked up the Venom symbiote in the device Spidey would find it in years later were coming to Earth at last. Cue invasion, Spidey realizes that this for once is a bit more than one Spider-Man can handle, so he calls in his brother-in-arms Kaine. Freeroam as acer said, co-op, etc. Have the moral system show up with both Spider-Men, i.e., with the Venom symbiote having rebonded to Peter so he could fight back against all these Symbiotes. If Peter makes a Black Suit decision, have Kaine make a corresponding Red Suit decision, such as reminding Peter that this is not him, or vice versa, setting up the final battle for either an insanely out of control Kaine, who was secretly bonded with an extracted Toxin symbiote in case Spidey went rogue, or a brutal beatdown of normal Kaine with Symbiote powered Peter, ala Cole versus Zack at the evil ending of inFamous 2. Make sure to encourage the bond between the two in the story, so that they are nearby for each major decision.
I'm thinking also Deadpool hired to take down Spidey and hand over the Venom Symbiote to the invaders, Bruce Banner having been called in to examine the symbiote's psychological effects due to his expertise with super powered dark sides, and being locked in the city, only for a Symbiote Hulk to be unleashed. Maybe Madame Web (Julia Carpenter) appearance, some Fantastic Four and Daredevil action, etc.
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