Phoebe Chill, second-to-hardest difficulty (blood and dust?), Naked Brutality start, reloads enabled.
You can learn how to trivialize most singular raids/events on youtube, so I like that Phoebe gives me "perfect storms" so that I have to make sacrifices or be very creative with how I solve problems, but generally my colony doesn't get completely wiped out, but it also gives me the breaks necessary to prepare for the bad events.
Can't imagine playing with no reloads. Managing even a medium-scale battle of any complexity is such a slog in this game, and way too often I will play through a battle and only realize after the fact I've completely forgotten about another corner of the map where everything's burning to the ground and half my colony is dead because I didn't have fire at will on or something.
Naked Brutality feels like the best story to me. I like to just run with whatever pawn gets generated first and I try to work with their strengths and find friends that can help asap. Not very good for your own ideology though. Normally I end up adopting whatever ideology my social pawn is.

