And too many people are quick to suggest others have not already bounced ideas around or offered suggestions before. There have been several posts with varying ideas on how to address the concepts of challenge and difficulty in the post level 50 game. This is not a new discussion topic and this subject was brought up not only here, but on live as well on many occasions.
What difficulty and challenge mean are subjective and those definitions vary from person to person. I can only speak for myself here - simply upping HP, damage, toHit, resists etc. on enemy NPCs does not equal challenge or difficulty. It simply results in a stalemate which is boring. I would much prefer not know what happen and tossing in a few random things here and there.
Were it me - and granted this is pie-in-the-sky wishful thinking - I would look at improving the underlying AI that would allow NPCs to be more adaptive to your combat tactics. I would also be interested in toying around with the idea of giving NPCs more coordinated strategies along the lines of what @Galaxy Brain mentioned up thread. Enemy NPCs never seem to use any strategy like ambushes or coordinated attacks. Another idea would be to introduce some random events into encounters, such as traps or even collateral damage. Collateral damage somewhat loosely already exists in mayhem missions and can either be a detriment or benefit. Think of using the environment to your advantage or in the course of your mission, your battle sets the building on fire and you now have to rescue civilians. You could also have random named NPCs or signatures spawn.