Now, I know that cultists are (sort of) the default villain in CoC and in this version, they still are. However, what if the investigators or a group of cultists themselves ran across something much worse?
For the investigators, perhaps the main worry is an extremely dangerous cult that desires to summon one of the outer gods in a demented play for power or a deliberate attempt to destroy the world, and must rely on the help of cults who are either saner or just less suicidal than the antagonists to stop the ritual and, depending on how disparate the motives of the two allied factions, either a long term acquaintance or a backstabbing gun battle over the spoils of victory can be conducted.
For cultists or other Mythos forces, either a "peaceful" cult of farmers or holy men, a traditional cult that works in the shadows and follows a "only sacrifice jerks" philosophy or non-human actors like mi-go, ghouls or deep ones could be played. They antagonists could be anything from a murderous corporate army, the doomsday cult of the first example, a traditional mythos-based enemy or a murderous band of fanatical, anti-Mythos investigators. A group of investigators would be actively sought out early in the game after some initial horror role play which would indicate that their faction is being targeted or hunted. From there, just have fun in foiling your trackers and staying alive.
In either situation, the gulf between the Mythos based mindset and the normal human SAN of the investigators should be played off of whether for laughs or drama. My favorite line is that of a Shub Niggurath cultist making a vow to his investigator ally in a show of demented camaraderie.
"I shall sacrifice the first prisoner to the health of your firstborn!"
So... Ideas, criticisms, praise? I personally prefer lovecraft lite and humor and usually have no stomach for the obsession on cosmicism, but the idea seems sound no matter what your playstyle.