What could possibly be the downside to applying yellow covers to your Prof. X? There is no negative part on his power like there is with, for example, Carnage black.
Back when Charlie’s Angels were the bee’s knees I remember some people mentioning building 5/5/0 Professors to use on the team since yellow made Black Widow’s Purple Power more cumbersome. So that’s at least a reason why you may want to avoid it. I don’t know how big a deal the Angels are these Days though…
3* Black Widow can only turn basic tiles into green, so if there are a bunch of special tiles around, it makes it harder for her to keep making the match-5s that the team runs on.