I think the biggest challenge in making an animated pixel art movie or show is how underdeveloped pixel art as a medium is.
Pixel art is only a few decades old, and it was all but completely abandoned by most of the game industry 20 years ago. And the vast majority of pixel art out there is for video games.
Animation also used to be a daunting and challenging practice. But after over a century of animators and producers perfecting it, developing techniques of animation and production to make it easier, look better and be quicker and cheaper to produce, it became an established medium.
Pixel art animation just needs to be developed more as a medium.