Dosn't even have to be fantasy d&d style.
Players are henchmen of Dr. Yes fighting super spy 00Awesome
Players are aliens serving a queen/hivemind that must defend a ship from space marines or other "good guys"
Players are zombies, nuff said.
Players are cultists, must summon evil deity, avoid investigators and sanity loss.
I actually wrote a small scenario where the players are fantasy henchmen (goblins, ogres, etc) and they have to defend a dungeon from a group of adventurers. The only advantage the players would have is that the adventurers must be extremely arrogant and follow standard player logic.
The first part of my scenario centered around the various jobs and duties the players could perform to get ready for the heroes. Some jobs included trap setting, preparing hostages, creating weapons, joining random patrols, and other stereotypical duties. Then, depending on how well they did on their jobs the players would either have a hard job defeating the heroes or a really hard time defeating the heroes.