Please don't kill me, these are merely my opinions on the subject of Mass Effect's future!
Honestly, we all know that the Mass Effect franchise won't end with the third game, however epic or conclusive it feels. Bioware has stated this is basically the end of Shepard's story, and I'm okay with that. Provided they dlc-fix his fate, I'm okay with this being his final outing. Beter he goes out in a glorious fashion, rather than be dragged on through more games until he's grayhaired, such the fate of Ezio in the Assassin's Creed games. Instead, I hope they can find a ingenious way to continue making more these action/sci-fi/rpg games.
Here's the direction in which I believe Bioware should head towards.
Basically, Mass Effect 4 should be to the franchise, what TNG did to Star Trek. Take the best elements, jump the story ahead 100 years or so, and see what's become of the galaxy. By now, the races of the Milky Way galaxy have united to defeat the Reapers, and the legendary Shepard has long since passed. But the former protagonist will always be remembered for his/her valiant deeds.
The new protagonist, here's where it gets fun, instead of just deciding the gender, you can also pick the race! Like Dragon Age, where the Grey Warden experiences different origins based on the chosen race, so will the Mass Effect 4 protag. You can stick with a male/female human, or expand the horizons with a Turian, a male/female Quarian, a Krogan, an Asari, or a male/female Drell. Customization would differ if you pick an alien, can't change the face really so you can instead customize skin color, designs, or scars. Powers and classes would be the same, but each alien has a differing origin, slightly altered in regards to paragon or renegade.
The protag would be a captain of a multi-race ship for the Council, the SSV Shepard, Vakarian, or whatever (can choose the name as its dedicated to a character from the first trilogy). The ship has many characters, some of which are part of the party. The make-up and fate of the galaxy depends on saves from the original trilogy, so Shepard's decisions reverbirate even into these games. These include if the genophage was cured, the Quarians or Geth were saved, the Rachni were saved, or the Reapers destroyed.
Whatever races survived will be part of the council, which now includes all races in the galaxy. They also created a less stable but effective means of lightspeed to get across the galaxy, dark energy! Peaceful since the end of the Reaper invasion, the protag's ship comes under attack by strange new aliens and tech that is unstoppable. The ship will be assigned to find and stop these new foes, and the player believes this will be another suicide mission like ME2. That's where they get a shocking suprise. After a few missions to prepare in the milky way, the fight against the new threat begins. But faster than you can say Stargate: Universe or Lost in Space, the battle against the aliens causes the ship to travel through a strange means of warp, which hurtles the protag on the surviving crew into a whole other galaxy!
Now faced with unknown worlds, races, threats, and no way to get home, the protag's mission is to gather supplies and allies in order to get back.