One thing I learned is to not using a meme as a punchline. If the meme is little know, the joke will go over people's heads and if it's too well know people will be sick of it. Hitting the sweet spot is mostly luck.

Worse, some people just deeply dislike memes so using one will always bother them.

Still, you can hide a meme on the back of a panel or something like that, and I think it's a nice use of it for people who know and enjoy memes, but just repeating it hardly works.