Planescape/Spelljammer Hybrid (including the Astral Sea stuff that Hexmage mentioned). Why? Because it completely expands the range of what D&D has to offer, and also provides a means to connect the worlds. It really is a no-brainer and almost past-due at this point. The problem is that it really requires several products to do it justice, and that doesn't seem to be what WotC is about these days. That said, I remain hopeful, if not optimistic, that 2022 might be "The Year of the Planes".
Honorable mention to Dark Sun, because it also expands 5E by offering a darker, more sword & sorcery vibe -- something really lacking from 5E right now.
I also agree that Greyhawk and Mystara fit more into nostalgia products, which is probably not enough reasons to consider as "shoulds." But it would be nice for both to receive commemorative products in 2024. I see Dragonlance differently due to its identity as a "story world," and thus it fits closer to what 5E is about, with its emphasis on stories.