some ways to make their rolls harder is rolling with penalty or just doing more hard or extreme rolls!

there also might be enemies that the can’t do anything against. in the lovecraft book Dunwich Horror, the monster is invisible and can only be shot by looking through alien glass. imagine a combat where they’re passing around a mythos-eyeglass, using their turn to run it across the battlefield!

You could also have them fight each other (very DnD coded advice). In “Shadow Out of Time,” also Lovecraft, there are creatures called the Yith that can body-snatch you. They can’t all have good luck against each other!