I'd pitch a good old fashioned European inspired fantasy setting with everything including the kitchen sink. The generic fantasy aspect will better ensure the game has broad appeal to D&D players and it would allow most D&D classes, species, etc., etc. to be compatible with it.
I'd start with a decaying empire which is still the dominant political force in the setting. They're a Romanesque culture ruled by Tieflings, the descendants of (mostly) humans who made a pact with demons/devils a millennia ago in exchange for power. In order to avoid controvery, this Romaneque culture doesn't explicitely engage in many of the activities the real Roman empire did, but it can be implied.
The region of the world the campaign is set is outside the empire, but they still have to deal with it by paying tribute and suffering their presence. There's multiple kingdoms made up of all manner of D&D species, except for gnomes and halflings. The gnomes resisted the empire and were driven to near extinction. You can still play a gnome, but you're one of the last of your people. The halfings are protected by the empire everywhere they go, but they're not permitted to own land anywhere, and travel quite frequently never sticking around in one place. Any species that isn't normally in the area can still make an appearance because they might have come from another part of the empire. The dragonborn were originally created as shock troopers for the empire, but as they retired from a life of soldiering, they retired to all parts. It's been generations, but a lot of people still see them as foreigners and a lot of the dragonborn don't really feel like they fit in anywhere.
Of course there's the remains of the old empire. Where else are you going to find ancient artifacts and dungeons to delve?
Aesthetic is Star Wars, Star Treck, Firefly, and Galaxy Rangers and other cartoons of that era, all had a baby, and the animation studio that brought it to life was the same as the Avatar cartoons with collaboration from the creators of the new She-Ra.
A thousand years ago, great empires spread across teh expanses of the galaxy using the Great Star Lanes, which were stable wormholes connecting one point in space to another along a visible beam of light. Inside the beam, time moved and matter existed as it did outside, from the perspective of the travellers, and you could even see magical creatures like star dragons riding along the Star Lanes, colonies of kobolds living on their ancient forms.
The Great Human Empire had gone to war several times in it's attempts to expand into other territories, but had finally joined the Galactic Federation of Free Worlds as a member state, and peace seemed to have come to the galaxy at last.
Then the Star Lanes collapsed and dissapeared, and travel between stars was suddenly impossible. Empires went dark overnight, worlds struggled to find sustainable equilibrium without access to other worlds. Some managed to keep advanced technology and live spread around a solar system, while others simply collapsed entirely and reverted to early industrial worlds or even further, before rebuilding sometimes with dramatically new and different identities.
Over centuries, new technologies rose up, and slowly, civilizations learned to communicate across the deep night of empty space, and then shared knowledge lead to new travel technologies, wildly different from region to region. The Goblinoids built solid-fuel rockets, while the humans used ionized gas impulse engines using mixtures of the aether gas that accumulates around gravity wells with various other gases and empowered by magitech power distribution and transfer, while the fey related folk of the growing Commonwealth of Free Folk build great ships with sails that collect solar power and trap aether gas, feeding it into secret engines of crystals and magnetism and spinning armillary spheres powering core crystals rumored to be semi-sentient.
FTL is dangerous business, and requires scouts flying alone into the deep night to place anchor points between stars, which then create routes that slipstream and other FTL ships can follow fairly safely.
Just as Galactic Neighbors greet eachother again in peace, an enemy arises. The core worlds of the old human empire quickly ally with the Commonwealth, eventually forming the Commonwealth of Free Worlds. However, the old outskirts, known once as The Baronies, however, had quietly formed what they called the Foretold Dominion of Humanity, an expansionist and xenophobic empire bent on the destruction and exploitation of any power outside themselves.
The old human core worlds are now known as the Borderlands, as they are the only practical path between the Dominion and the Commonwealth and the greater galaxy, and the Rangers of the Borderlands patrol in fighter jets and their Knights follow in powered suits of armor with magitech computer intelligence called Angels. The Borderlands have become a diverse place where the bravest and best of the galaxy meet to fight a seemingly endless war against an enemy that see all of them as monsters to be destroyed.
Meanwhile folk in the Commonwealth are protected by Andaron Rangers with their magitech personal enhancements and sentient magitech mounts, and the Knights of Lumin with their personalized gear and esoteric secrets. Both groups, and other smaller groups, travel the free worlds helping those who need it, solving local problems, and acting as warrior-investigators, councilors, diplomats, and usually possess skills that are useful in a more mundane context, like mechanical repair, computer operation, animal husbandry, or agriculture. They're here to help.
Recently contact has been made with the Arkhosian Fleet, which seems to be a flotilla nation of dragonborn and other draconic sentients, whose home star systems were not hospitable enough to house the growing civilization, and so they became experts in external habitats and colony ships. They bring news that the Dominion is also trying to expand in the direction opposite the Borderlands, and Arkhosian space has recently been inundated with refugees as the successor states to their ancient enemy, the empire of Bael Turath, stand as the sole serious defense against Dominion expansion.
Just as recently, the Illithid Republic has made contact and overtures of peace and alliance, but those overtures have been soured as Rakma rebels come to the Commonwealth as refugees, warning of the mind control, domination, and destructive hunger of the Illithid and their Elders.
As all these factions seek stability and to understand the new landscape of a galaxy they only know from ancient records and folk lore, a Star Lane reactivates connecting the heart of the Dominion to the jewel of the Core Worlds, a star known as Aumonautor and it's 13 inhabited planets, and the Borderlands War has gone from constant skirmishes to massive battles nearly overnight. Aumonauter Prime is in ruins, and it's heroic legions scattered to other worlds, though most continue to fight.
Now, another Star Lane has opened, connecting the Commonwealth and Arkhosian space, and another connecting the Feylost Nebula to Goblin space.
Over several years, the galaxy has been overturned again, and nothing seems certain, or safe. Still, many greet this new state of things with hope, while others pragmatically use the Star Lanes to establish more slipstream anchors and prepare for another collapse. The human worlds are at war, but they have more allies than ever as part of the New Commonwealth.
tldr; all the big empires fell when star lanes closed a thousand years ago, they rebuilt over 1000 years making new tech that didn't rely on the star lanes, main non-human but human looking races created a Commonwealth, some humans joined it but others formed an evil empire called the Foretold Dominion of Humanity that is trying to take over the galaxy, there is a draconic empire and the illithid are trying to present themselves as helpful friends but rebels from their empire warn that they're evil as hell. Every civ has different ship tech, from rockets to ion impulse drives to magitech airships with crystal cores surrounded by armillary spheres that few understand, to whatever else can b thought of. Aether gas collects around gravity wells, and can be used for fuel, turned into power crystals, or grown into core crystals, and it makes it so that airships can travel in space.
Multiple good powers and regions of space are threatened from the outside, and sometimes from within, regular folk need help sometimes from wandering heroes, and the only way to make it through is to believe that love and fellowship and folks helping folks, can save the galaxy.
Everything in dnd has a place here, but it's not the same place as in other settings.
new race: Atroposi - a deaths head mothlike race that can subsist on aether gas and lives in asteroids and planetoids normally. Flight, heightened vision and hearing, ability to make other creatures frightened, and possibly to speak with the dead at level 5 or whatever.
New classes and subclasses: same as island worlds, plus a sabotuer rogue subclass, an Angel Knight Captain fighter, an oath of The Commonwealth paladin, a jedi-like monk subclass, a ranger with a sentient construct mount and magitech enhancement.
A lot more telekinetic and telepathic abilities.
New mechanics I'd want to see would be expansion of bonds to give players Contacts they can call upon, and a system of favors and assets they can call in or spend, and an expansion of ship combat, as well as a huge expansion of equipment, weapons, vehicles, etc.
For space combat and vehicles, i'd prefer the single person craft should basically be magic armor, with some special rules, rather than a starting point of building a vehicle. You gain DR, THP, a new Speed, new weapons, new AC calculation (an interceptor fighter would calculate like really good medium or maybe even light armor, while a beefier fighter would just have an AC value like heavy armor.
Ship and gear customization, without going near as complex as Star Wars Saga Edition.
It'd be cool if they made my homebrew setting into a WotC setting so that I don't have to fund the art for it. Anyway, the basic tropes for it are:
Multiple worlds on the material plane
They are all connected by magical transport (teleportation), the ethereal, and the astral.
Teleportation between the world's is safe and reliable, but costly.
The ethereal and astral are much harder to traverse in their own ways.
Teleportation can only reach worlds within a certain distance. Traveling between them can be as simple as one teleportation or needing 5+ teleportations.
Each world has it's own "thing", like reduced gravity, mostly destroyed, 98% water, is a massive underground vault, etc.
Each world is the origin of a species, though some worlds might have 2 or 3 native species.
Playable species only cover a portion of their respective worlds. Much of each world is uncharted.
The gods of creation have long gone and new groups of younger gods reign from their ethereal or astral domains.
There is a lot of mistrust between the species. War, subjagation, and colonization are common.
Otherwise, give me a modern setting. Make sure it's a new world. I don't want modern Forgotten Realms. Give it a late 90's or early 2000's level of technology alongside magic. Each class should have a modern variant with the same basic idea, but updated for the technological difference. Probably limit spells to 5th level to avoid shenanigans (more lower level slots to make up the difference) and make new ones to interact with tech. New skills, weapons, vehicles, etc.
WotC doesn't need new 'settings.' They've got a multiverse. Just pick a spot and tell a good story there. Don't create separate branding for different 'settings,' which will just lead to people not buying the book because they don't play that setting.