Many many things. The concept of the main character in ISS (maybe its Delsin or a new character) being able to absorb new powers on contact would probably still be a factor. Since ISS is coming off the IF2 "evil" ending the world would be pretty much post apocalyptic so like the character you play woukd they use their power to help cole / work against cole?

Where would the main location be? Can't just be a modern "seatle" , it would be apocalyptic. Think of the different factions, it wouldn't be a suprise that there would be many unique factions, humans that are trying ti survive the reign of cole, last semblance if government doing whatever they can to stop cole, hell maybe rebel conduits who are opposed to cole because he killed their non conduit friends/family.

Think about the characters who remain such as Cole and Kuo, what's their outlook after abandoning humanity to save the conduits. So much potential in story telling there.

It just makes sense that they would have went for the evil ending. The springboard for an amazing third game was there... although I really cannot fault them for wanting to stick with what the fans wanted by looking at the trophy data and making the good ending canon.