The team at BioWare responsible for developing Mass Effect 4 has a daunting task ahead. The original Mass Effect trilogy is highly regarded, and the recent release of the Legendary Edition is a reminder of the high standards Andromeda couldn't quite live up to. As a sprawling and complex science fiction epic, Commander Shepard's story through the trilogy deals with the fate of all life in the Milky Way galaxy. The main villains, the Reapers, are about as evil as an antagonist can be - harvesting all life in the galaxy every 50,000 years in an ill-conceived plan to preserve the life they're extinguishing.
When approaching the task of writing a follow-up narrative to Mass Effect 3, its no wonder BioWare opted to set a new Mass Effect game in a whole new galaxy. Especially on the heels of the massive galactic war against the Reapers in Mass Effect 3, most other threats pale in comparison. The premise behind Mass Effect Andromeda was actually pretty smart. An entirely new galaxy gave the developers a clean slate, far removed from the Reapers, and plenty of questions regarding Shepard's fate and the state of interstellar civilization in the Milky Way could be ignored for more immediate problems.
On the other hand, turning around and creating an even greater threat for Mass Effect 4 would feel contrived. It's natural for the stakes to increase with every sequel, and the original trilogy handled this well with the Reapers starting as a mystery before their actions led to a full-blown invasion in Mass Effect 3. Turning around and making an even greater threat to the Milky Way in Mass Effect 4 would feel more than a little forced, which puts a sequel in a strange predicament.
Mass Effect 4 Doesn't Need A Reaper Equivalent Antagonist
Attempting to release a sequel over a decade after Mass Effect 3 is ambitious. Not only does the narrative of the original trilogy have to be respected, the developers will be competing with plenty of nostalgia, especially since the Legendary Edition has refreshed players' memories on the strength of the originals. Mass Effect 4's trailer appears to be setting up the game as a continuation of the original trilogy, which provides the opportunity for a more grounded story. Regardless of which Mass Effect 3 ending will be made canon, the aftermath of the war against the Reapers will have to be dealt with.
A significant time jump could attempt to avoid the subject entirely, but the untold number of casualties and the power vacuum likely created after the Reaper invasion make for a compelling backdrop of post-war galactic politics. Humanity-first organizations like the Terra Firma political party and Cerberus are likely to make power grabs in the immediate aftermath. Reconvening the Citadel Council would be difficult with so many pressing issues on the invaded home worlds and colonies. The Terminus Systems might take the opportunity to invade Citadel space while militaries are scattered and crippled.
There's been no information yet on when exactly the sequel will take place, but the the Mass Effect 4 teaser trailer indicates its at least within Liara's lifetime. Long-living species like the Asari tend to deal with political matters slowly, so it's very likely the game will have to address the issue of a post-Reaper narrative head on. Releasing Mass Effect: Legendary Edition was a good restart, but recent misses like Anthem and Andromeda leave BioWare's ability to truly deliver on Mass Effect 4 still something of an unknown.