I've had a fascination with a Gargoyles & Gravel / DnD-style MvM. Players would fight skeletons and various fantasy/mythical monsters in a stage-based campaign. For developers, there is a lot of creative freedom, but would be very content heavy (i.e. You'd need to build a world, items, monsters, scripts, coding, etc).
The biggest difficulty is it might not very replayable since the content is baked into the map, so getting other creative eyes set on making their own campaign would be (technically) difficult. (You'd probably can only go as far as something like Mutations for L4D, I'd assume?)
I tried with my own map before VScript, mvm_berserker. People have tried to make content for it, but I haven't asked why it never fruited anything. I assume it was too complicated (due to multiple spawnpoints for bots for different rooms, various Hammer-logic spaghetti...) or simply buggy.
Overall, this would be a big technical undertaking to make it replayable, requiring a lot of time, planning, and dedication.