A prequel could be interesting, though, with humanity first finding the Prothean ruins on Mars, and struggling to grow in power among the newly found alien races… hmmmm.
I'm halfway through my 2nd full play of ME1/2 to get "my" Sheperd prepped for ME3, but AFAIC the Protheans have pretty much lost any semblance of being interesting anymore.
First, as was discovered at the end of ME1, most of the really interesting tech wasn't created by them-- they just found it and used it like we did.
Second, they were basically failures, not only in elevator construction, but also in their ability to do anything, politically or militarily, to save themselves against the Reaper onslaught. As a PC, why would I want to go back and participate in that world, knowing that no matter what happened, they were doomed?
And 3rd, who wants to see humanity struggle to be respected by other aliens... Again... Been there, done that.
I'd like to see a game with new characters (or even Shepard if he isn't
really dead, but I assume that's off the table) just going around and exploring, which to me has been the best part of the series. Landing on new planets, adding actual space ship-vs-ship combat, and if they want a huge story arc, have it deal with taking down Cerberus (or helping them, up to you), figuring out more about The Collectors, or even continuing the Reapers story as it seems there's a lot left to wrap up (so I'll soon find out).