The BioWare that made the original game is gone, so it's probably best to move on. They've already retconned half the lore and swept the other half under the rug when they made Andromeda. But if there was a sequel, I'd like a Mass Effect 4 (ie. chronologically after 3 and in the Milky Way). I do actually have an idea I'd love to see, tho I know it'll be EAd. It starts by removing Andromeda from memory and ignoring it in canon entirely, but like Andromeda, the only piece of information it will ask for from the OT is Shepard's sex for reference. ie. It will be new and not account for
any prior player decisions.
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Mass Effect 4 is set about 150-250 years after Priority: Earth. The Destroy ending is canon, whether Shepard lived or died in the attempt is ultimately irrelevant. Shepard is remembered as a hero, the first human Spectre who ended the Reaper's reaping and wiped out ALL AI (at least at the time). So no reapers, no geth (no EDI 😞

. I would further retcon the destruction of the relays so they are all still in tact and working. Don't even mention it, just pretend it didn't happen.
Two things I would want to see more than anything is a) we can play as a non-human. So we can pick a character to be asari, turian, or human. Options could maybe include Salarian/Quarian or maybe Krogan, but not sure if that would work or be too complicated (the first three can share two voices, with a synth for Turians). b) I want to see Dragon Age: Origins' ORIGINS back. So what happens, the player can pick their race, their sex and their class (yes, bring back classes). So the Asari would be a huntress, the Turian could be a specops or covert soldier, the human an alliance or CSec maybe. There should be 5-6 different Origins and this forms the Prologue/Tutorial like in DA:O with some player choices that have repercussions down the road. There should be a difference between the races, such as Asari get +Biotics, Turians get +Tech but can't learn biotics, etc.
Whatever happens in these Origins, the player becomes a SPECTRE tasked by the Council to investigate something. During the adventure, we'll return to Rannoch, where we see the youngest generation of Quarians able to walk without envirosuits. We get to visit Tuchanka where we see green returning to the world and children being born. These two things are the payoff for fans of the OT. While most OT characters would be long dead, we could have Wrex, Liara and Aria return for brief cameos, maybe Grunt or Samara. Liara would be a matron now, in the second phase of her life, Wrex would be really elderly, maybe at the end of his life, perhaps he's spent the last decades grooming Grunt to lead Urdnot and the allied tribes, who have now become less warlike.
To be honest, the plot could really be anything. A mcguffin, a new alien species invades the milky way, someone creates a new AI race (tho I'm loathe to see it go back down that road). Maybe the Leviathans wake up and set something in motion. If I were to outline something, some ideas could include finding one outpost full of thousands of surviving Protheans...perhaps Javik is responsible (were Protheans long-lived, I can't remember?). When they wake up, they reactivate some ancient technology of theirs and start a militant campaign of conquest. Another idea could be that an Asari separatist movement want to secede from the Council, blaming the other races for Thessia's fate in the Reaper War, and they form a...well sorta a Cerberus type organisation, terrorising council space and taking over asari colonies. Perhaps they're Ardat-Yakshi who enter open rebellion, banding together.
There's no story that can up the stakes from the Reapers, so I don't think they should try to. Something no more than Death Star threat level will be just fine. Maybe they could portray the galaxy still in turmoil, struggling to pick up the pieces 200 years on with the Batarians practically extinct, the other minor races like volus/elcor considering siding with non-aligned parties like Aria in Omega because they've lost faith in the Council. Maybe there's a while rival government. I like the Prothean idea personally; Ilos is the inspiration for that...maybe Javik, as a soldier, went investigating some old outposts, found intact cryopods at one and unthawed the former general of the Prothean military, who had secretly seeded many thousands of loyal troops, scientists, women, etc in their cycle and done the same thing that Ilos did. Javik, realising his mistake seeks out Liara and the two of them bring the threat to the attention of the Council who send the player out to investigate.
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With all that said, while the franchise was originally shelved, seemingly indefinitely, Casey Hudson returned and took over the top job after EA fired the numpty that made Andromeda. He said he wants to revisit it and was the original executive producer so there could be some hope there. My main concern is that Drew Karpshyn is no longer there and he was the main creative force. Mac Walters gave us the nonsense stories from ME2 and ME3, and all the plot holes, retcons, starchilds and Kai Lengs that went with it, along with Andromeda. I do not believe Mac Walters is a good writer, at all. Further, it will inevitably be EAd, meaning tacked on multiplayer, always online, Origin, lootcrates, etc. I want it to return to the structure of ME1 and abandon the Andromeda pseudo-open world structure.
Andromeda also highlights the difference in approach to storytelling and world-building. In ME1, we learn in-game and in the codex about biotics, the Normandy's stealth system, relays and the "mass effect", the genophage, how shields work, infinite ammo guns, etc. Then in Andromeda...they crossed galaxies...because they did. They identified "golden worlds" 2.5 MILLION light years away...how they identified them is anyone's guess, they just did. Somehow frozen krogan woke up cured of the genophage because handwave. They're completely fine with AI despite how dangerous it was portrayed until then. They not only retconned or tore up lore, they didn't even replace it with anything.
Shamus Young described it as going from "details first" (like Star Trek") to "drama first" (like Star Wars) and the world really suffered for the change. And I don't think they're capable of going back, but I'd like it to.