First off, I do know that the game is done, so this is a fond wish-type thread, not a "dev pleasepleasepleasepleasdothisthing!" thread.
Now, a lot of people are saying they want harder difficulties with intelligent AIs, but not just bullet sponges. We can reasonably assume there will be multiple difficulty levels. After all, every Bethesda game I've played has them, and most games in the world does too.
I dislike the concept of more hit points means more difficult. That isn't the case. It makes it more frustrating. Damage done shouldn't change regardless of the difficulty. The difficulty should be in having to be more methodical and deliberate in action.
My thoughts would include a variable to the range that Perception detects an enemy. At lower difficulties your Perception could pick them out pretty far away, but at higher difficulties you would have to be pretty close to notice them. Say just outside their visual range.
Another thought would be an increase in enemy accuracy. Lower levels would be Stormtrooper-esq levels of hit ratios, while at the highest you'd have enemies that are hitting you about 70% of the time.
Mobile enemies are also a good way to go. At the lowest difficulty setting, enemies would only jog slowly or walk. While at the highest difficulty, you'd see them sprinting, changing direction, or even backing around corners.
Thoughts?