I've been kicking around an idea for my next Mutant Future campaign: humans as an endangered species. The folks that do all the important stuff in the campaign would be plants, animals and robots. In some areas of the world humans would be considered mythical while in other places they might be second class citizens or treated as animals like in Planet of the Apes. Other communities might never have heard of humanity. The PCs might care about the fate of humanity and the campaign could even be about that, but humans (mutant or otherwise) are not what the milieu itself is about. The world of 2525 (or whatever) just doesn't give a crap about humanity anymore than the world today cares much about any of a hojillion extinct species. They're dead and we've moved on. Later we're dead and they've moved on.
There'd still be morlocks somewhere, of course.
Would this set-up annoy you as a player? I'd certainly be open to letting folks play PCs who were some sort of the last remnant of humanity, whether that means mutants slumming about radioactive ruins or cryogenically preserved pure strain humans. But I wonder if this sort of heavy-handedness might make the game ungrokkable to some players, especially the neebie types.