This is just a set of ideas for ya, (don't know if they've been done before as I've never played mixing fantasy with the West) but considering guns. Guns might fire something other than lead ammunition or shot. They might fire magic missiles, fireballs, or other types of exotic ammunition. You could have guns and other tools than are similar to magic items in D&D. By that I mean maybe even intelligent and experimental weaponry
Indians might play the part of Elves, being excellent survivalists and trackers, and many would probably make superb modified Ranger types.
You might even have a squad of Texas Indian Rangers.
You might have Bear and Wolverine warriors who were Western equivalents of "berserkers, " or Bear-shirts.
Clerics and Paladins could be circuit riding Preachers or even French-Canadian Priests who have moved south and into the Plains. Paladins might also be Vigilante types trying to assure Frontier's Law and Justice in places without a real law enforcement presence. Pinkerton agents might also serve as Paladin equivalents.
Thieves would run in packs and gangs as outlaws. Rangers could also be anything from Army Scouts to actual military raiders or reconnaissance agents or spies.
Bards could be Jack of All Trade types or could even be newspaper reporters operating undercover. Or they could be traveling Mountain Men storytellers or even Indian shamans. Shamans and medicine men could be clerics as well.
Magic users could be technological experts, and/or sorcerer types
You'd have a lot of room to create original, one of a kind, dangerous monsters, even supernatural ones, like a Vengeful Ghost who is seeking the man who murdered him for jumping his claim to a mine. There could be Western Vampires, and so forth. (I actually saw an old movie about that one time, about a Preacher in Black who shot to death a vampire out West by attaching a cross shape to the end of the silver bullet he fired. An Ogre in a cave near the desert that everybody thinks is a wild and vicious bear. A werewolf in the badlands. Swamp Creatures. Things that could change shape to appear human hunting prostitutes and Johns out of saloons and whorehouses.
You'd have a very interesting mix of people types, Indians (both hostile and allied), Settlers, Mexicans (both hostile and allied), European immigrants, Chinese from California, cattlemen, farmers, cowboys, mountain men, ex-Military, Express Riders, and so forth and so on. And you'd have various business and corporate concerns, the railroads, ranchers, farmers, bankers, businessmen, the military, smugglers, organized outlaws,
And of course you'd have a huge, built-in base of interesting historical characters and NPCs to fill out the background.
Depending on how it is done it could be extremely interesting.
Good luck.
