The Commonwealth (and Institute) is certainly my first choice, but I also think it would be tricky to use well. If the Commonwealth comes in to play late in the game I think it will feel too much like the Enclave and if you start there it will feel too much like the Vaults. Despite this, I think it would be great to see a somewhat successful attempt to rebuild after the war.
A game set almost entirely within Boston is particularly tempting, but I must admit I've wanted Bethesda to do a more urban game for some time. Focusing more on the problems of a burgeoning civilization is particularly appealing. However I think a lot of people would be unhappy that there was so little open wasteland, and a more urban environment would also likely mean more underground areas, and the DC subways were hardly popular.
... pardon me, I'm having an epiphany ... a concept is streaming in ...
Set FO4 in the Commonwealth - maybe twenty or thirty years before FO3. The Commonwealth is just a wasteland, with a few pockets of survivors scraping out a pitiful existance. Kind of like in FO3.
Your character hails from the Institute - or rather, the private Vault built beneath it. S/he will be part of a project aimed at reclaiming the area, and rebuilding society after the War. As such, you're sent out into the wastelands on missions of various sorts - scavenging supplies, scouting, bringing settlements under Institute control (and thus, providing a steady stream of renewable supplies, like food, to the Institute), clearing out threats, recovering antiquities (the Museum of Fine Arts, the Isabella Gardner Art Museum, and various historical landmarks and museums would provide a lot of fodder for this).
The tone and character of the Commonwealth you build will be determined largely by your own moral choices; do you take the Evil path, and engage in conquest, extermination, and theft? Or do you take the Good path, and build bonds of trust through diplomacy, mutual assistance, and cosmopolitanism? The former would lead to a Commonwealth of unscrupulous, self-centered nature; the latter, a Commonwealth that lives up to it's name.
That lets you have a large, detailed urban landscape ... but ALSO have lots of wide-open spaces. There're also islands to consider - right in the Harbor, even. Yes, the inevitable subways as well (Boston is home to one of the oldest continually-operating subway systems in North America). And ... if vehicles are doable ... boats, to said islands, and even other locations. Heck, that would open the way for missions dealing with PIRACY ON THE HIGH SEAS, even!
:)