Hmm, as far as the setting, I'd say pick something that sounds interesting to you as a dev since you'll spend so many hours working on it, you don't want to work on something you aren't passionate about or it will likely end up being an abandoned project. A number of base story settings are kinda overdone right now, but I can just tell you what I'd personally be interested in.
* Semi realistic in terms of the characters, their personalities, etc (think City of Broken Dreamers - each character is pretty well written with unique personalities)
* I personally would love to see a game where you have to work for the sex a bit - don't get me wrong, having the girls interested in MC is good, but having to impress them or otherwise pique their interest a bit in-game is a plus. I'm just not a huge fan of every hot girl in a given setting lust after the MC for no discernible reason - it makes the game setting tough to immerse myself in.
* I don't have a lot of specific fetishes (I like a little bit of everything in terms of the scene content - vaginal, anal, girl dresses up, girl dances in sexy outfits, many different positions, etc.), but one I'd really like to see done well is a game where one of the LIs is actually the MCs sister (if she could be gorgeous like Jenny in AOA Academy that would be awesome, lol) - but a story where it's actually semi believable and not have her lusting after the MC 10 mins into the game - maybe circumstances in the story give the two characters an opportunity to be closer to each other for whatever reason, etc. and "stuff happens" and actually have it turn romantic, not just a fling, etc.
Just sharing my views for you, hope it helps and best of luck on your game.