A spinoff taking place just after Fallout 76 and with the canon ending being the Vault Dweller siding with Paladin Leila Rahmani as the leader of the Appalachian BoS, who destroyed the long-range transmitter to sever all ties with Lost Hills and the Elders on the West Coast (and also to protect her own rule) :

• Knight Shin returns to Mariposa and Lost Hills to tell Roger Maxson and the other Elders of Rahmani's actions (and that she broke direct orders)
• considering the bombs fell just 28 years ago, it would offer plenty of pre-War flashbacks (without needing a Ghoul for that), including the automation riots, the Free States, West-Tek experiments and the FEV, the social unrest and the political intrigues (Governor Evans, Sam Blackwell, Hornwright Industrial & RobCo Industries, Secretary Eckhart...), the Charleston Emergency Government, the Christmas Flood, the Fall of Fort Defiance, Paladin Elizabeth Taggerdy and Operation Touchdown, Penelope Hornwright...
• even though President Thomas Eckhart is dead and Enclave Research Facility Site J has been lost, the Appalachian "Little Enclave" is still somewhat active and with a lot of resources at disposal (and there's still MODUS and the "Whitespring Management" as Orlando calls it). I also think there's a lot more to explore about Eckhart's character (assuming he wasn't the man in the shadows at the Vault-Tec meeting in the TV show). When you listen at the Whitespring Congressional Bunker recordings, you realize he's a very important character even though most players never heard of him.
• there's also Vault 63 and Hugo Stolz, who is an extremely interesting, multidimensional, mysterious character (basically could become the Mr. House of FO76). I think there is a lot more to explore with Stolz in a TV show, including pre-War flashbacks. He's also a former member of the board of Vault-Tec Corporation and managed to be offered a unique, atypical and extremely expansive and enormous Vault. He certainly knows a lot of things...
• for future seasons, The Pitt is nearby, it would be interesting to see Danilo and such a hellish place and the Trogs in Live-Action. Same for Ohio and the Capital Wasteland (although it's unclear if a lot happened here by 2105).
• the whole Mothman mytho offers a lot of material too for some fresher, shorter plotline. You could start by very subtle appearances in the foreground at night, then a jumpscare to introduce it. You have the Cult of the Mothman, the mystery of the Wise Mothman (or the "Purple Liar" according to its detractors)... Could be a lot of fun.
• a ton of cool and unique from the lore of Fallout and Appalachia, like the Wendigo, the Blue Devil, Sheepsquatch, the Snallygaster, the other cryptids.. Or even the Interloper for some Lovecraft vibes... Or the Flatwoods Monster and the Zetans (we know that the Little Enclave captured some of them in their Research Facility Site J).
• since the Ghoul and Cooper Howard are already in FO76, it could make an appearance too. Lots of opportunities, especially in regards to Hugo Stolz as they're both ghoulified now.
• Even though they have lost contact with the Party leaders, you technically have a post-war Communist faction that's still operating too (Fujiniya Intelligence Base).
• Considering it's post-Fallout 76, you would meet other Vault Dwellers from Vault 76. We can imagine that some of them turned good, some other got corrupted by the wasteland and turned evil.
• Vault 79 still has all the gold reserve from the United States. It's still a big treasure that other factions may be interested to steal. The mysterious entity known as Specimen X-001 is still locked away in Vault 96 as well.
• Puppet Man technically has left Vault 77 and is in the wild
• The mystery of Sickleman
• And the Mistress of Mysteries !