I have a theory about Mass Effect 4 that I think might be plausible. First of all though, I'd like to start by declaring that this is NOT simply another ME3-fueled rant. We all know how ME3 ended. We all know about the community backlash. We all know about Bioware's cryptic announcements and 'false advertising'.
That's not the point of this thread.
MINOR SPOILERS AHEAD
I will take a moment however to mention the Indoctrination Theory. I was a big advocate when I first heard about it, and I still am.
I'd always felt uneasy about ME3's end sequence; it was all too surreal, not quite right. IT explained almost everything coherently, and in my opinion transcended ME3's finale from a crushing disappointment into a potential masterpiece: a pinnacle of meta-gaming and an unprecedented literary achievement.
Ultimately, Indoctrination Theory was neither confirmed or denied by Bioware, who instead opted to leave the ending "thought provoking" and "open to non-literal interpretation". Even if true, the theory itself remains just that: a theory. It's still plausible and MUCH more profound than the ending we got otherwise, but to be concrete it needed to be consolidated by an actual end-game: a chance for Shepard to withstand/succumb to Harbinger and end the fight for better or for worse. Contrary to what many have said, the lack of post-breath confirmation doesn't actually disprove IT, although it does leave the actual ending entirely up to the players' imagination.
But what if Bioware do actually have additional plans to expand Mass Effect 3's ending? Not via DLC or an online press release, but with a sequel? Or a spin-off of some kind?
I recently watched this Rocket Chainsaw video regarding an alleged PAX ME4 marketing conference during which several sample questions were posed to long-time fans. I believe that it may actually be credible, and if so then several points stand out:
- An emphasis on N7 (identity, concept, iconic equipment, etc). This would only be a valid marketing concern if either the new protagonist is yet another N7-level human special forces operative... or Shepard will be making a return in some form.
- An emphasis on discovery and acclimatisation to new surroundings. This could mean anything; exploring new worlds and civilisations... or simply adapting to a post-Reaper wasteland in search of food, materials or shelter ("Fallout 4: Milky Way" style).
- The omission (or 'downgrading') or several familiar species. The video narrator thought this might be related to protagonist options, but I think it's something else.
- Gauging fan interest in a sequel (!). There are legit business reasons for a direct sequel to ME3 (even if that sequel doesn't turn out to be the ME4 game currently under development):
- Bioware may want to finish their story, but they need to restore their public image.
Indoctrination Theory is a trump card, even if it wasn't their initial intention (although it's well known that they did play around with the idea of physical indoctrination, and some elements of the theory are just too damn coincidental to ignore). It's way too late for ME3 of course, but providing a satisfactory conclusion to the story elsewhere may mitigate the damage to their once-impeccable reputation, and improve sales of both preceding Mass Effect games and future titles.
- EA is always seeking additional income, often by drawing out existing projects and selling them piecemeal. They may have had the bright idea of turning the epilogue into a fully-fledged (and fully-priced) sequel. EA want to retain consumers just as much as Bioware do, and a full sequel that gives the fanbase everything they asked for and more would be a win for every party involved (although that wouldn't take back the broken promises).
- Bioware may want to finish their story, but they need to restore their public image.
Bioware of course have been very secretive about ME4's setting and story, only really hinting that Shepard would no longer be the game's protagonist and that a direct sequel to ME3 is unlikely.
That said... If you were working on a sequel to a game that you implied there wouldn't be a sequel to, in order to sell content that was promised to buyers of said previous game, then you'd want to give the fanbase as much time as possible to cool off before asking them to pay for something they should already be entitled to. That's probably just wishful thinking on my part. 
Anyway, my theory about ME4; I'm going to assume that IT is a valid interpretation as Bioware themselves have stated. This is just my personal prediction (which I'm doing for fun after all):
- It'll be post-ME3 ("one more story", Mr. Aldrin...).
- Survivors of all species are now stranded in (or entering into) the midst of a "galactic dark age" (Mac Walters' words) following the extensive destruction wrought upon their respective civilisations by the Reapers. If this is actually the case then I'm betting a post-apocalyptic Earth will be front and centre.
- Some species have been hit far harder than others (for example, the exposed Quarian Flotilla in space). This is likely related to the 'species omission' hinted at above by the Rocket Chainsaw video. Canonically devastating certain species and reducing their presence in-game would do two things:
- Add some real gravitas to the setting and alter the inter-faction dynamics somewhat, keeping things fresh. Allegedly Bioware will be incorporating two all-new races as well.
- Reduce Bioware's workload (if certain factions can be omitted somewhat, then the two new factions can be introduced without the effort of doing so hindering development or increasing costs too much).
- Add some real gravitas to the setting and alter the inter-faction dynamics somewhat, keeping things fresh. Allegedly Bioware will be incorporating two all-new races as well.
- The game could take place weeks, months, years, decades, or even a century after the events of ME3 (remember, the Protheans took almost two centuries to eradicate).
- The player may be able to select their protagonist from a number of different species (I seriously doubt the protagonist would be anything to do with "N7"). Although if this meant going the Dragon Age route with a silent protagonist, no thanks.
- A number of variables in the game will likely be affected by your ME3 saves, as implied by comments from Mike Gamble. Maybe certain gameplay elements could be linked to ME3; for example, the results of your Quarian, Geth and Krogan story arcs could determine their initial availability as protagonists or allies.
Further speculation:
- The Crucible has been activated (for real this time), and the Reaper threat has been mitigated... but not eliminated entirely. Due to Earth's proximal position to the Crucible, it may become a galactic base of operations (especially if the Reapers there have been bit hardest by the Crucible).
- A protracted war for survival (and later, ultimate victory) is still raging across the Milky Way, as unified guerillas across the galaxy put up the greatest resistance the remaining Reapers have ever faced.
- Lacking their previous strength following activation of the Crucible, the Reapers may have adopted a different modus operandi:
- Maybe they're attempting to sabotage the Mass Relays one-by-one and compartmentalise the different solar systems for easier eradication.
- Maybe they've built up a veritable army of indoctrinated agents and are fighting a counter-offensive guerilla war of their own, using them to assassinate galactic leaders and undermine resistance defences. Finding new methods to detect indoctrination would become extremely important for the survivors (like dogs in the Terminator franchise, or the classic blood tests in The Thing), and could have extremely interesting implications for Shepard's character (if present) depending on the players' choices in ME3.
- Maybe Bioware could even re-introduce dark energy as a narrative element, as a vital resource for the Reapers to feed upon for example. We already know that both Object Rho and at least one Mass Relay (both Reaper-built) have used dark energy for that purpose. Hell, maybe the key to defeating a Reaper is using Element Zero or mass effect fields to starve it! It was all in the title!
- Maybe they're attempting to sabotage the Mass Relays one-by-one and compartmentalise the different solar systems for easier eradication.
- Shepard's story (as well as those of his associates) WILL be extrapolated in one of two ways:
- Proactively, with the player taking control of Shepard as a protagonist once more. Even if only for a brief period (eg., Altair in AC: Revelations).
- Retroactively, via exposition alone. Shepard has become a legend of biblical proportions; an invincible warlord, fallen hero, inspiring diplomat... tragic villain... whatever. His exploits (and possibly downfall) are history, and the repercussions of his actions referenced throughout the game.
This would be the more efficient (albeit slightly underwhelming) way to end Shepard's narrative; every single choice and player variable could be accounted for in depth without the need for anything but text and casual NPC dialogue. The results would be extremely comprehensive without blowing up Bioware's workload.
- Proactively, with the player taking control of Shepard as a protagonist once more. Even if only for a brief period (eg., Altair in AC: Revelations).
Concept art for the game is starting to emerge, so I guess we'll find out soon enough.
Sorry for the lengthy post; I had fun writing it and got carried away. Despite the ending, Mass Effect remains my favourite series of all time, and I get very passionate about it ("lots of speculation for everyone", right?). 
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