One of the most exciting possibilities for a possible new campaign setting book would be Planescape. Arguably, this already has some detail in even the core books, with the Dungeon Master's Guide giving descriptions of the various inner and outer planes.
The various "outsiders" found in the Monster Manual, and also found a lot in Mordenkainen's Tome of Foes, also gives us examples of monsters to use in these settings.
So the thing I wonder about, as a player who has played D&D for about... six years now? But one who has not been steeped in its lore since childhood like some others, is where the general understanding of the planes ends and where the Planescape setting itself begins.
I did buy on DM's Guild a 2nd Edition Planescape Campaign Setting book (published in I want to say 1994.)
The core focus of that book (I think the very first Planescape book came out in 1987 or so) was on the city of Sigil and the Outlands, which are the outer plane usually ignored in the "Great Wheel" charts given that it sits in the center, though not to be confused with the center that is occupied by the prime material plane.
Really, it helps to think of it as a 3D model rather than a 2D chart. You can think of the Outer Planes as existing above (or, if you prefer, below) the inner planes, with the Outlands at their center, and then the Inner Planes existing on a different vertical level, this time with the Prime Material Plane really at its center.
This cosmology has changed with different editions - 4th Edition really upended things and had the "elemental chaos" as the location for several planes including the Abyss, but 5E has generally held the four elemental planes (which are kinda sorta one big plane, with border regions that mix those elements) as separate, Inner Planes from the Outer ones.
The Planescape Book features a mostly familiar cosmology with the Great Wheel even illustrated quite dramatically as a kind of giant pie with the Outlands as a sort of circular piece in the middle and the city of Sigil orbiting (it's a ring-shaped city that only has an inner edge, and gravity basically goes "out") an impossibly tall spire coming out of its center.
My sense is that if you're talking about the Planescape setting, it primarily refers to Sigil and the Outlands. The extent to which Sigil is "in" the Outlands is sort of a matter of interpretation - the only way to reach Sigil is through magical portals; you can't go there traveling, you know, spatially.
The Outlands, beyond Sigil, are also really interesting. One of the premises of Planescape is that a region can literally become part of a different plane if enough people or activities embodying a different alignment congregate in that area. If the demons invading Avernus were to truly dominate the region and drive the devils back to a different layer, Avernus would become part of the Abyss (though dang, if that place isn't chaotic evil already...)
The Outlands are the True Neutral plane, shaped like a big disk. Around the plane, there are "Gate Towns" that allow passage into all the other outer planes. But given that, and the way that the planar mechanics work, each of these towns needs a perfect counterbalance. For example, Automata, the town granting access to Mechanus (which was also sometimes just called "Nirvana") is the super-rigidly structured, lawful neutral town you'd expect... until you find the crazy bacchanalian society that exists underground, which keeps Automata from simply becoming part of Mechanus and, you know, ceasing to serve its purpose (the Abyss gate town of Plage-Mort is apparently new because the old one got sucked into the Abyss.)
Culturally, the Planescape setting also has some interesting notions - particularly to the city of Sigil, which has its own very special and odd rules. For one, its ruler, the Lady of Pain, is basically infinitely powerful, at least inside the city, and she bars any and all gods from the city, and can erase a god and every one of its worshippers if they try to get in (also, do not, under any circumstances, try to worship her as a god. It will not go well for you.) The city is run by a number of "Factols," which are factions that are actually somewhat analogous to the guilds found in Ravnica, each with a fervently-followed and often strange philosophy.
People from Sigil are a bit like people from New York (caveat: I like New York and New Yorkers, and this is said more as a native Bostonian with a bit of a chip on his shoulder) in that they look down on anyone not from there. In particular, "Inners" from the Inner Planes and, above all, "Primes," meaning people from the Prime Material Plane, are seen as dumb hicks from the boondocks. Unlike my home city of Boston, Sigil can actually make a reasonable claim to be the hub of the universe (it's even shaped like a wheel!) so you can see where they'd get the inflated hometown ego, but still.
While the Outlands and Sigil are obviously really cool locations, what I'd argue is the biggest appeal to the setting is that all the planes are open to you. Really, the entire D&D cosmos is the setting, which could range anywhere from The Uphill Climb, the one operating tavern in Caer Dineval, Icewind Dale, to the palace of Everlost, in Thanatos, the Demon Lord Orcus' layer of the Abyss.
Actually, an interesting note: in the late 80s and the 90s, the rise of "moral guardians" (particularly the Christian right) singled out Dungeons & Dragons as a particularly dangerous practice for children, believing that its depiction of demons and devils would encourage satanism among kids (frankly, I think the vast majority of people who identify as satanists today do so because of the hypocrisies of the religious right, but that's not what I'm here to talk about.)
While for all I know this boosted sales of the game, TSR (which owned D&D before they were bought by Wizards of the Coast in the late 90s) decided to rebrand somewhat. The Nine Hells were renamed Baator, and devils were renamed "Baatezu." Demons were renamed "Tanar'ri," and daemons were renamed Yugoloths.
Once the Satanic Panic wound down, WotC brought back the pretty standard, recognizable fantasy creature names (except Yugoloths, which stuck probably due to how confusingly similar their names were to demons.)
Now, I don't know if this is just a relic of the fact that the sourcebook I was reading was from the early 90s (and that was probably the case,) but even though those names were created as a concession to a repugnant social movement (one whose effects we continue to suffer) to be honest, I kind of like how it redefines the outer planes - less the classical heavens and hells of various real-world mythologies, and more like alien worlds that we'd better not make too many assumptions about.
Planescape is cool, which is sort of half my point.
The thing is, while it's a very cool setting, I'm always interested in tools to homebrew concepts and mechanics. I don't know if I'll ever be able to match the massive amount of detail that has been poured into the Planescape setting, but when I first started designing my own setting, I took the license to create my own multiverse and ran with it. So while my Tartarus probably shares a lot with The Abyss, I'd really enjoy some more general mechanical concepts for planar adventures.
I think the plane that most fascinates me is one of the inner planes - the Shadowfell. This plane has actually only existed since 4th Edition, being a kind of merging of other concepts from earlier editions that was, canonically, merged in the massive events that took place between 3rd and 4th Edition.
There was a 4E book about the setting, and I've been tempted to pick it up on DM's Guild. But in more general terms, I wonder if there's a place for a book that's less about the specificity of various planar settings - less about telling me about specific NPCs and dungeons found on a particular giant gear in Mechanus than giving us monsters and environmental mechanics.
Actually, thinking about this, I couldn't imagine making a book that ignores such specifics. But the real question is how broad such a book could get in its subjects.
If we look only at the Outer Planes, we still have 17 entire universes to explore. If you take just the Nine Hells, that's still, you know, nine layers that each have their own different locations. Baldur's Gate: Descent into Avernus, finds enough content for levels 5 through 13 on just the first layer.
So I have to imagine that a book that tried to give details about all of the Outer Planes would wind up only being able to touch on each briefly.
That being said...
The MTG crossover books (and to an extent the Eberron book) are broken down in a rather clever way. (For the sake of my typing fingers, I'm going to just call these by their setting names.) Ravnica has chapters divided by guild - there's a chapter for player characters of each guild, one for adventures that involve each guild (and broader suggestions on possible villainous plots by those guilds as well as missions the players might be sent on by those guilds) and the treasure and monsters, also divided by guild.
Theros does the same with its pantheon of 15 gods.
So perhaps a Planescape book could do the same, but focusing on each of the 17 Outer Planes - with sample maps, monsters and NPCs that you'd be likely to find in those planes, some extra playable races (bariaurs, for example) and maybe some subclasses, and you've got a comparable 5E setting book.
Honestly, I would not be surprised at all if we get something like that in 2021.
However, while I think this would probably get a lot of fans in a nerdy frenzy to grab the book, I feel like the Inner Planes get neglected.
I guess it's an open question: would players be more excited for an updated, 5th Edition version of the Planescape setting's most iconic elements, or would we want something a bit newer, focusing on aspects of the D&D cosmos that haven't gotten a lot of attention?
Screw it, I'm going to get that 4E Shadowfell book on DM's guild.