Y: The Last Man has two issues that focus on a theatre group trying to make important work about the post-Gendercide world. Their first effort is not received well. Later they try films and comics. Also, a supermodel whose profession is obsolete and is now clearing bodies (a minor character from early in the story) gets a issue later on.
Peter David, fed up with the Wolverine Publicity that drives the X-Men franchise, once wrote an issue in his X-Factor featuring none of the usual cast, instead focusing on popular characters like Wolverine and Cable.
In a similar vein, Walt Simonson wrote a three-issue Fantastic Four arc (with art by Arthur Adams) in which the FF are temporarily replaced by the four most over-exposed (during the 90s) characters in the MU: Wolverine, Hulk (during his gray-skinned Mr. Fixit phase), Spider-Man and Ghost Rider.
The classic Uncanny X-Men story Kitty's Fairy Tale. The cover even featured Kitty Pryde announcing, "And now for something completely different!"
The shift from the Brian Michael Bendis Era Avengers to the Jonathan Hickman Era is a very noticeable example. From the more accessible, Bendis-voice-filled Avengers to the more high-concept, sci-fi Hickman Avengers.
After Joss Whedon took over Runaways, he veered sharply away from the usual storyline of the Runaways dealing with some Monster of the Week by sending them back in time to 1907, where Victor falls in love with a local girl, Chase and Nico discover that an earlier version of the Pride is trying to start a gang war, and Karolina and Molly try to rescue a young girl stuck in an abusive marriage to a much older man.