I think, if they're going to stick with America, the next setting should be an amalgamation of the Southern US states and Northern Mexico. This would include Vice City (Miami, FL), a GTA version of New Orleans and a GTA version of Dallas. There would be swampland with gators and pythons, and desert with coyotes and antelope. Possibly even some temperate areas with bear and elk. There would be a ****-ton oil drilling in the desert. In the Texas/Arizona area, there will be rich-*** ranches to loot and wildlife to hunt. There will be a border fence and constant border jumping attempts taking place. Possibly even missions to undertake from both sides of the fence, such as border patrol and border crossings. Mexico will be rife with drug wars and gangs. There will, of course, be tons of Cartel violence and drug running missions.
One of the main characters will be a Mexican representative of the Cartel. He will come to America on Cartel business and decide to strike it big himself.
If we go the multiple character route, at least one of the characters must be female. Rockstar is a stickler for realistically representing their characters, so this must be a female character that we could see holding her own in a world like GTA's.
One possible angle that could be played would be that two of the playable characters could be in a relationship. This would lead to an interesting dynamic, possibly even a Bonnie and Clyde-type experience This could play out to be very exciting, especially if you were able to use the quick-swap between characters option outside of missions as well. Throw in couch co-op, and you could have a game that could also bring in the couples demographic. Maybe there could be four or more playable characters - two or more women, and two or more men, so that any couple (or individual) could play any pairing of characters they desire. For one, playing as two separate characters together, even outside of missions either by yourself, or via couch co-op would add enough to the experience by itself, but having the ability to play as multiple combinations of characters will add many layers to both the storyline, and gameplay styles.