Some setting that some super popular streamer has, tbh. Or some random mtg setting
Ah, you said "classic" setting. Well, that's a bit different. I'm not even sure Nentir Vale qualifies, but I'll let that slide for now.
So "should publish" is a fraught phrase (say "fraught phrase" 10 times fast). Ie, from a business standpoint? From a fan-service standpoint? From a "creative" standpoint? Maybe I'll try to answer all 3, in reverse order.
From a creative standpoint, I think a Planescape/Spelljammer mashup provides the biggest canvas area for expansion. It can expand beyond just Sigil and also allow both a "default" multiverse setting as well as provide rules to DMs who want to create their own. The full breakdown of the inner and outer and demi planes can be explored in depth. There's all kinds of places, beings, factions etc to delve into.
From a fan-service standpoint, if I was to only go off of ENWorld, it feels like there are top level desired settings like Dark Sun, Greyhawk, Planescape, Dragonlance, and Spelljammer; and then other less popular settings like Ghostwalk or Birthright. So for maximum fan-service, go for one of those 5. Someone up thread said that having settings like FR should probably take them out of the running, and I agree that probably crosses off Greyhawk and DL. If you mashup Planescape and Spelljammer, you cover 2 fan-desired properties at once!
Finally, from a business standpoint. As you can see I'm angling for a PS/SJ mashup. BUT, I believe PS intellectual property is partially owned by Tony Diterlizzi? Maybe not, that might be fake news - happy to be steered right on that. But if he partially owns the IP, that could be a hurdle for any sort of PS setting or adventure book.
However Planescape and Spelljammer also fit into the overall MTG Planeswalker concepts; and could potentially provide an in-canon link to the MTG planes. Which could result in the greatest thing no one expected back in 1995, a Blood Wars/Magic the Gathering release. Wow.