IMO the best thing to do, and the most fitting from both a story perspective and also from "refreshing" the game design, would be to make the refusal choice the canonical ending to Mass Effect 3.
That ending is the most "fitting" end for Shepard and the storyline imo.
There was no real way out with the other three endings, they were all sort of twisted in terms of forcing a choice on the species as a whole with the others, or turning shep into a reaper himself, ugh.
Shepard wouldn't have done this, he would have bit his lip, accepted the loss and told them to shove it and went out fighting.
Having Liara's "backup" plan be the thing that actually saves future civilizations from the reapers seems both fitting and bittersweet, even though Shep and the rest died and didn't "win" then and there, it was because of their journey and everyone on the crew coming together that allowed for them to actually be the ones that in the end save the day even if they were long gone.
This also paves the way for new stories and frees the game up from chasing "reapers" and things.
We can have completely new species in the galaxy, new gameplay designs for things, and the story doesn't have to be so focused on saving "the universe" but rather can be a more personal story that sets up things for future games.
I'd love to see a more focused game with the ability for you to actually fly around in a ship, land on planets (from space), have a smaller crew BUT be able to play with all of them and take them exploring, have vehicles to use, go back to allowing you to outfit your crew and things, etc.
Think of something more in line with say, Firefly/Farscape or something in terms of scope/story and crews on your ship.
