Other than 3D comics I can't think of much else in regards of use of medium. There is a webcomic called Weaker Sides which mixes media, using traditional, digital, and photography. Although this is the only comic I've found so far which does this.
There are a few unique uses of a common medium, like:
Seluda taking a 60's-70's abstract approach.
There Was a War having a less conventional comic layout, and using a surreal look reminiscent of Celtic folk art.
SUPERPOSE is going for a cinematic look with some VHS aesthetics thrown in.
The Dogs on the Railroad (I assume) is an MS Paint comic in B&W, with everything having a more grungy look that's unique to the program.
There are more, these are just the ones I remember off the top of my head.
As far as niche genres/subgenres, I'm not sure what you already have lined up but the ones I know of are usually grim dark stories, tragedies, comics featuring hard to swallow topics. I would even consider horror in itself to be a niche genre within webcomics at least, they are very few and far between. At least comics that are full on horror, and not another genre with horror themes. There aren't a whole lot of classic nerdy sci-fi comics out there either. (ones similar to Star Trek and such)
There are also weird niche porn comics, but I don't think you want to brave those ones.
As someone who's webcomic is within an uncommon subgenre (dark psychological drama), and being someone who's for freedom of creation, I really like niche stuff. Depending on the type of story, they can be very cathartic to make a read. Some people need, and can handle the heavy, weird, problematic stuff.
