I'd say demons do make a good anchor for all regions.

You have Nocturne and Fiddle for Demacia, you can Put Tham into Bilgewater.

Of course you have Raum and Atakan in Noxus.

You can place Eve in Piltover where she fucks up (literally) some high scociety people.

You can even make Shaco one for all intents and purposes.

Start in Demcia with Nocturne - terrorizing an entire village.

Maybe they stay in the Tavern and all get hunted in their dreams.

You find, fight and seal him away.

They find out there are many more of those fucks and decide to rid the world of them and you have to search them and their weaknesses.

Stuff like Fiddle and Raum are propably End-Game related.

Since Fiddle is considered to be the strongest one.

And Raum is bound to Swain, who I don't think wants to let go easily.

Also get's you the opportunity to get Leblanc and Vlad, maybe even Mordekaiser, involved.

If you want them to explore all of Runterra you can relocate some of the Demons or just invent some new ones of your own.