Another advantage of an in-house theme is that you're not as likely to be predisposed towards one faction.
Part of me says I'd like to see games based on themes that I personally like. These differ for each person, but for me this includes several miniatures games such as Warmachine/Hordes or Infinity. On the other hand, one problem there is that players of the minis game have strong faction loyalties. For instance, in Warmachine/Hordes I play Menoth, Skorne, and Farrow (which is basically half of the Minions faction) so clearly these would almost certainly be my favorites. Some factions I'm fairly ambivalent about, and other factions I actively hate like Cygnar and Retribution.
So if it was a single-faction game, at least two factions worth of cards wouldn't get used at all, and quite a few more might be used rarely. This isn't a good value for me as a player if they release the typical Core set + packs. It might work if they immediately do faction boxes for each faction, but even then at some point I'll probably be forced to buy what will for me be "dead cards". Some of these faction cards might be used if you can take out of faction stuff but I'd still feel resistant to a lot of them I suspect.
A theme without strongly-established loyalties seems better in this respect. How do Warhammer: Invasion players deal with this today? Or has GW's practice of rotating the "strong factions" trained people to be more willing to switch loyalties?
Personally I'd love to see a space game with warring races, or something themed around ancient China with kung fu clans, magic, etc… Yes, I know about L5R but I don't really like it and anyway it's collectable. Both themes also seem friendly to being able to field mixed faction decks representing temporary alliances between races/clans/whatever. On the space front, I was originally favoring Babylon 5 but then I realized that Star Control 2 would be an awesome theme to do - they've always had such a fantastic array of alien races with different ship powers. Problem there is TOO many factions I think.