Let me clarify; I meant a sandbox style game. Although you can always end the game before an Inquisitor's death, with them going off to deal with the next crisis, maybe with subtle hints that what you've had to do is beginning to corrupt you.
Actually, an RPG in which the struggle was as much to avoid becoming corrupted and jaded by what you've had to do while still trying to do your job sounds like it could be very interesting. Hmm... Does anyone have any idea what Dark Millenium is shaping up to be?
The real issue with a Skyrim-esque game in Sci-fi, I think, is that you'd start to run into the problem Bioware had with ME 1 and SWTOR; When you have dozens of planets in a game, you either end up with a relatively boring, bland, computer generated look for most planets (ME 1), or the areas end up small and somewhat constrained (SWTOR). Limiting yourself to only a few planets on the other hand, and people complain you haven't used the full depth of the setting... Although, actually, if you do a system with multiple habitable planets, that's actually pretty suitable for 40k, given how long warp travel takes.