It's not just VTM, I also have some fun #DungeonsAndDragons ideas I'd love to try.

Like a party of paleontologists and biologists who take a scientific approach to various monsters and how they came to be.

Or a game that starts mostly normal, but a few weird things happen, around level 15 or so things start coming together as forces from Stargate Command show up through a sacred ring and Jaffa start landing and oh this world with all its races and magic was a Goa'uld experiment in enhanced hosts. Have the barbarian firing a Javelin at a Tarrasque and the archery rogue introduced to the Barrett.
The latter one would be a very hard needle to thread. There would need to be dramatic weight to the suddenly O'Neill events, that would be hard to do if the players know it's coming. But pulling a genre shift on that level without advance buyin from the players is a bit cringe, I've been in games where the DM just randomly gave us Powerpuff Girls powers out of nowhere and that was just not the game I signed up for.

I'd need to have several games under my belt with at least a few players in this one having played in my games that would have enough trust in me that when I say "something huge will change as we approach endgame" it's going to be significant but also somewhat thematically tied to how things were from the start.