In two years, WotC will be releasing a new set of core rulebooks. They have not said explicitly if this is going to be D&D 6th Edition, though it would fall on both the 50th anniversary of D&D and the 10th of 5th Edition, making it a good symbolic time for something big and new. That said, 5E at this point is a fairly potent brand, so I wouldn't be shocked to see them try to downplay the idea of its being a new edition. Likewise, they've said that these books will be "backwards compatible" with previous 5th Edition releases.
We are seeing some books effectively rendered obsolete - Volo's Guide to Monsters and Mordenkainen's Tome of Foes are listed as "Discontinued" on D&D Beyond due to the fact that their update in the form of Mordenkainen Presents: Monsters of the Multiverse contains all the same monsters with revised stat blocks (both books have a fair amount of lore within them, but I suspect that much of that lore is actually due for a revision as well - such as the idea that not all Drow are Lolth-worshipping cultists).
At a fundamental level, I think there are a few questions to be asked about the mechanics of D&D. There are ideas that were introduced in 5th edition that those of who started with that edition kind of take for granted. The proficiency bonus, for instance, is a very useful catch-all to indicate greater skill with certain things. Given the way we've seen subclasses and racial features lean in further to use the proficiency bonus (including things like the number of times you can use an ability per day) I think that's likely to stay.
But rather than get into a full nitty-gritty idea of what fundamental mechanics will remain the same or be changed, I thought I'd look at the major character choices - primarily Classes and Races (Backgrounds I think might get a bit of a rework, so I'll save that for later).
Races:
As someone who started with 5th Edition, the races in the Player's Handbook seem like the obvious go-to options. At this point, anyone who has played the edition will likely think of Humans, Elves, Dwarves, Halflings, Gnomes, Tieflings, Dragonborn, Half-Orcs, and Half-Elves as inextricable from the game, even if we have some options (like Tieflings) that were introduced long after D&D was first introduced.
The first question here is how much room there is for races in the book. If I had my druthers, every race featured in Monsters of the Multiverse would be presented as an option in the core rulebooks (I'd also like Warforged to join them, though I understand that WotC seems hesitant to make these a setting-agnostic race).
One thing I think we're likely to see changed is the elimination of subraces - in Monsters of the Multiverse, the subraces of PHB races like Duergar, Eladrin, and Deep Gnomes were turned into independent races that simply share the "dwarf," "elf," and "gnome" tags as part of their creature type. This might have been done simply to account for the fact that they were not going to be publishing the baseline dwarf, elf, or gnome in the book. But they also did this with the Genasi and the Gith, simply putting all their features in each category.
Much of what once defined races and subraces was their ability score improvements, so I think we might see some races revisited to give them a little more substance.
Of all the non-PHB races that seem to see a lot of republication, I think Goblins stand a strong chance of being made an option in the new Player's Handbook. As one of the ubiquitous presences in D&D, Goblins have, like a lot of "monstrous" races, seen a revisitation, rehabilitating them as peoples worthy of dignity who are not all evil. If you asked me to guess what race could be bumped up to a core, PHB race, that's probably at the top of my list.
That said, I also think Orcs are a pretty strong candidate as well. Another staple of the fantasy genre, and likewise a classically "evil" race (in Lord of the Rings Orcs and Goblins are just two names for the same people) that, in more recent media, have been somewhat rehabilitated as complex people with free will, and whose historical conflicts with the "good" races might be seen as less a good-vs-evil conflict and more one bearing resemblance to the complex and ethically thorny conflicts we see in the real world.
Personally, I'd like to see more representation of mixed-race characters. In the 5E PHB, we have the Half-Elf and Half-Orc. The question, though, is how exactly to handle this kind of mixed ancestry. These half-X races, for one thing, imply that the other half is human. How does one represent a person who has a dwarf and an elf for parents? Or someone who is half-Halfling and half-Gnome?
This, of course, runs into the complex issues of trying to turn ancestry into a game mechanic.
Indeed, I'm tempted to, actually, just get rid of the "half-" races entirely and find some other way to incorporate mixed ancestry. I believe Pathfinder 2nd Edition makes being a half-Orc something like a feat that you can take when you make a character of another race. Not being familiar with Pathfinder's rules, I don't know how well this works. But I think it would be great to have a system in which we could reflect the broader diversity of mixed ancestries.
At the very least, I think that you could add the Monsters of the Multiverse version of the Orc, which has actually become far more flexible in terms of the kind of classes it can play (Aggressive now lets you simply dash as a bonus action a limited number of times, and you get the Half-Orc's relentless endurance).
In terms of the Dragonborn, I think that the updated Metallic and Chromatic Dragonborn races from Fizban's Treasury of Dragons seems like the obvious thing to transform these for the new edition. The question, then, is whether Gem Dragons are going to be thrown into the mix. While there are five core Gem Dragon types just like there are five metallic and chromatic options, my sense is that gem dragons, and thus perhaps gem dragonborn, are rarer. Perhaps those remain in the supplementary materials.
Lastly, I could maybe see the addition of Aasimar as a kind of counter-balance to Tieflings. I still think that Goblins and Orcs probably deserve a spot in the PHB more - one could argue they even deserve the spot more than Tieflings or Dragonborn, given that the PHB seems like it should include the really tried-and-true fantasy tropes.
Classes:
Given that Classes are the most carefully curated element of the game, I suspect that WotC will be very conservative with these. And indeed, if these new core rulebooks are meant to be backwards compatible with 5th Edition books, it seems you couldn't really drop any of the existing classes.
Over all of 5th Edition, we only got one fully new class that made it to publication, the Artificer. (Guys, remember how insane the Mystic was?)
I've made this argument several times already, but I think it bears repeating here: If the Artificer is printed in the Player's Handbook, it will open the door for the publication of additional subclasses in future supplements.
Indeed, the very concept of subclass has, I think, made adding new "classes" to the game far easier than it was in previous editions. With the strong "chassis" of, say, the Paladin class, you don't need to reinvent the wheel to come up with something new.
Some classes will want to see a bit of tinkering - I've written before about how I think that the Tasha revisions to the Ranger were mostly good, but the Favored Foe feature needs to be better. I also think that we could see the Fighter in general incorporate Maneuvers and Superiority Dice, which might mean a redesign or just elimination of the Battle Master subclass (given that, in essence, every Fighter would be one).
I know a lot of old classes, like the Avenger, were simply made into subclasses of existing ones (the Avenger became Oath of Vengeance for Paladins) so I don't know to what extent we can get a lot from plumbing the depths of older editions.
As I've said before, I'd hope that each class gets at least three subclasses to choose from, meaning we should shore up options for Barbarians, Bards, Druids, Rangers, and Sorcerers. Off the top of my head, I'd suggest putting Zealot, Eloquence, Shepherd, Gloomstalker, and Storm as the third options. While there are some subclasses from the PHB I'd be tempted to prune (Circle of the Land... does anyone play that one?) I sort of hope they'll instead receive fun redesigns that bring them in line with the mechanical quality that we've seen with more recent subclasses.
I think this is also a great opportunity to rebalance some aspects of various classes. Giving the effects of the Hexblade's Hex Warrior feature to anyone who picks Pact of the Blade, for instance, would be great. I'd also maybe remove the Bear Totem's resistance to everything to bring it more in line with other Barbarians.
Overall, I think my suggestions have been pretty conservative. For all I know, WotC is planning for a much bigger revamp. I'm also holding out a fool's hope that the reason Warforged were not included in Monsters of the Multiverse is that they're going to be in the PHB.
We're still a little ways out from Spelljammer: Adventures in Space, and the other books we can expect to come out in the remainder of 2022 and the books that haven't even been announced yet for 2023.