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 Also, a supermodel whose profession is obsolete and is now clearing bodies (a minor character from early in the story) gets a issue later on.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!"
Strangers in Paradise had a Superhero Episode, as well as a send-up of Xena: Warrior Princess, after it was pointed out by fans that Francine and Katchoo resembled Xena and Gabrielle. (Katchoo was less than thrilled to wind up as Gabrielle.)
Adam Warren started the last run of volume 2 of Gen¹³ by doing a whole issue in the style of VH-1's Behind the Music, featuring each character's fake demise in ironic ways.
Issue #34 in both series of Marvel's What If? were all-humor issues.
Also, issues 6 and 7 of The Mighty Thor volume 3. This volume is usually about the female Thor, but instead this issue is a story told by Loki to Dario Agger for Villain Cred reasons about a Viking he helped against the young Odinson in the 9th century AD which may or may not be made up. Jane doesn't appear at all, because she's incapacitated thanks to Avengers Standoff. This issue is also in a completely different art style.
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 Hickman's Avengers ended, the tone changed during All-New, All-Different Avengers, with a focus on teenage superheroes and a slightly lighter and softer tone more akin to the Bendis run of 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.
Jon Sable, Freelance #33 is about the children's books that Jon writes and tells the story of a group of leprechauns living in Central Park. Aside from a framing sequence, the art is by Sergio Aragaones instead of Mike Grell.
The Fantastic Four Roast (February, 1982) was a one-shot all-humor special where everyone in the Marvel Universe showed up at a fete for some good-natured riffing on the titular team. Written and laid out by Fred Hembeck, it took the liberty of changing why Dr. Doom became a villain and harbored such hatred for Reed Richards—in college, he wasn't invited to a panty raid with Reed and his college buddies.
Dr. Doom: If I had been invited on that panty raid, the Dr. Doom you see before you would not exist! I could have been a fun guy!
Ultimate Spider-Man: Initially, the comic book was starred by Peter Parker, reimagined as a teenager. In one of the stories some years later, The Hero Dies. Miles Morales, another teenager with no previous relation with Parker, becomes the new Spider-Man. It wasn't just a change of main character, but a change of secondary characters as well, as Miles had his own cast.
Ultimate X Men: Initially, the status quo was basically similar to the standard one: Charles Xavier has a mansion where he recruited and trains the X-Men, who go to superhero adventures, and Magneto has a villain team that opposes them. Things changed in Ultimatum: Most of the cast is killed off for good (including the four sacred cows, Xavier, Magneto, Wolverine and Cyclops), Storm and Collosus are jailed, and the X-Men break up and destroy the mansion in the aftermath. And it was also revealed that mutants are not the next step of human evolution, but common people with their DNA rewritten by nanobots. From then on, the comic became a Fugitive Arc.
The Ultimates were a reimagination of the Avengers, a government sponsored team of the most badass heroes around, that provides national security and got involved in international crises as a result. When they break up, the All-New Ultimates replace them. They are a street-level team of teenage superheroes, fighting against street gangs.
Rat Queens had one story where the party is working as freelance mercenaries in the ShadowRun universe as a Breather Episode after the Fleshwarper arc.
