My personal preference right now for a new setting is something modern - I’d love a D&D “setting” that basically puts D&D in the “real world” - scare quotes because all the same caveats around not dealing with real world politics if one didn’t want to apply. I was kind of toying with a New York or LA based game built around the idea that all the D&D PCs and NPCs are refugees from another dimension that was utterly destroyed but came to Earth by way of magic gates, and they’re trying to live amongst us now. Very V:TM in some respects with the whole living amongst oblivious normals but still D&D. Also, the artifacts that caused the destruction of the previous dimension also made their way to Earth and being sought out.
Of course this just opens up mechanics to new classes, modern weapons alongside magic, new spells, rules for vehicles and the like.