Big changes are a rocky proposition, and often, if you try to redefine an established character, it gets reverted down the road, if not immediately, because nostalgia, comfort, and sometimes folks just think the original idea was better. War Machine can't be an ugly alien armor forever, and Machine Man, eventually, had to stop calling people 'fleshy ones." So, what are some big changes that worked so well, they've been working more or less ever since?
For the MU, the grandaddies of this are probably Captain America being a man out of time, which, of course, wasn't part off his deal for over twenty years, but has framed him significantly ever since, and also, the more close-to-the-beginning change of Hulk going from a grumpy bully to an angry, easily emotional child.
Much as I love Stan Lee and Paul Ryan, I have to admit, Ravage 2099 was a pretty mundane title until Mills and Skinner took over and changed the tone of the comic, the look and powers of the protagonist, the supporting cast, and, well, everythin about the comic except the name and just started doing patented Pat Mills machismo, religion, and slavery are a bit funny aren't they? stories where Ravage was set on by big game hunters with slaves or running around massive and naked with a telepathic bat and a girlfriend with the powers of an Asgardian death god.
Back in,, say, 1992, who'd have thought that a fiercer, tactically-strong, charging-to-the-fore Sharon Carter would,, or could, be such a big part of Captain America's life? But since Waid and Garney brought her back - and she'd been dead quite some time - she's never really gone away, and she's never gone back to being "classic" Sharon.