Have a solid metaplot. The setting is less important than the actual game's plot, imo. You can have the coolest setting and premise ever but if the game ends up just being a bunch of random characters hanging out and living their lives (particularly if that living-their-lives thing is made too easy for them; not having to work or face any kind of adversity at all, etc), of course people are gonna get bored. A lot of panfandom games I don't even look twice at because they seem to have no metaplot going on at all - just slice-of-life jamjars where Tony Stark and Derek Hale go curtain-shopping or whatever. Which is fine if that's what people are into, but if you start a game where that's the only purpose, you either need to start off with a large dedicated playerbase or be really lucky. A metaplot (that you actually do stuff with and don't just have sitting there, ignored by players and mods alike) ensures that there's always something for characters to do when they get tired of the novelty of "omg! You're Batman! I love him!"
And, yeah: you want to start off with enough people that your game looks reasonably occupied - nothing turns me off faster than seeing a game with 40 characters only has like 3 players.