I gave up on El Goonish Shive when the artist dialed down the action and it evolved into a talking-heads comic.
I haven't given up on Calvin & Hobbes, but my feelings are definitely mixed. Calvin's dad hates the modern world and there's nothing he can do about it. Calvin himself is a misfit, and there's nothing he can do about it. The strip keeps pointing out what's wrong with the world, but it never offers hope that it could be better.
I gave up on Invincible around the time it showcased the alien blender-toilet. That was when the comic jumped the shark, but it was already swimming in that direction around the time the main character started agreeing with the genocidal superintelligent t-rex. With superhero comics, the main moral question is what to do with all this power that you're given, and Invincible stumbles by assuming you can fix the world with simple, sweeping solutions.
I gave up on The X-Files because it seemed like they would never wrap up the story and the characters would never get enough development. Like, Scully would always be too skeptical, even after all the weird shit she's seen, and the Cigarette-Smoking Man would always be needlessly cryptic. The overarching plot felt like it should've led to a massive Independence Day-style invasion, but that never happened. And after a while the monster-of-the-week episodes got stale. I do miss Assistant Director Skinner.