Halo 4/WMG

The Enemy...
The antagonists in Halo 4 will be a radical human faction that has exploited Forerunner technology and crafted unique armor, weapons, grenades, vehicles, ships et cetera...their goal is to conquer and annex the entire galaxy and rule it just as the forerunners did, which will bring them into direct confrontation with the UNSC and by extension, the Master Chief. They'd call themselves the "Sons of the Forerunners" or something along those lines.

They would present a new, fresh enemy in that your task would now be to kill rival human soldiers, but at the same time they are "alien" and menacing enough to be a major threat.


 * Reading the Forerunner Saga, I think it'll be the Flood (in more varied and Nightmare Fuel forms) and Forerunners (or at least their constructs, led by the Forerunner Master builder, who was never confirmed dead and was racist against anything that wasn't a Forerunner Builder, especially humans).

Locations
The new trilogy will probably explore the Greater Ark (the larger sibling to Installation 00) and Halo Installation 07 (which was used as the preserve dedicated for humans, but was overun by the Flood and is now a repository and memorial for constructs made of preserved human personalities)
 * Conventus Facility, as depicted by an ambiguous AI similar to Adjutant Reflex.

Spartan Ops guesses.
My guess is it will start out with pirates and move on to bigger threats.
 * Perhaps, some characters that are exclusive to Ops.
 * With the presence of a new Spartan team known as Majestic Squad, perhaps when having four players everyone will do something in cutscenes. With one player everyone else will be bots and only you will do things in cutscenes.
 * You might also be able to choose a voice for your character to use in cutscenes.

There will be a secret weapon that you can unlock after beating the campaign on legendary.

 * At the end of the game not only will you receive a legendary ending, but it will pull a MW3 and give you the option to go to Spartan Ops or something, then when you do so it turns black and a montage of a weapon will appear, it devastates enemy players in few hits and looks somewhat larger than your standard DMR, it is overall a large weapon that is obviously UNSC. It is a new gun that is like the Guass weapon on the Hog and the MAC, it is a experimental infantry Coilgun which the UNSC is testing to replace the weapons they already use. This can be placed in Forge (which most likely will return) and be one of those ordinance things.

Why the Elites are your enemies again
Controversial though Halo Glasslands may be, it introduces some serious conflict between the "mainstream" Elites led by The Arbiter and advocating peace with the humans, and the "Servants of Abiding Truth", religious fanatics who still blindly worship the Forerunners and want to resume war with humanity. Perhaps, in the years between Halo3 and Halo4, the two sides came to blows in a Sangheili Civil War... and the Arbiter's side lost. Now, with the human-friendly Sangheili higher-up and his supporters dead, the Servants of Abiding Truth have full control over the species again and have re-declared war against humanity.
 * More likely is that they are separate from the covenant and are openly hostile against anyone they don't like, or even more possible is that the religious anti human side lost and a large portion left in isolation to life amongst themselves.
 * I'm getting a Bermuda Triangle vibe from the game. Maybe they're just Covenant that got brought there years ago and simply don't know.

There will be more Marathon references
A given, but some will start to get to the point where you wonder where Master Chief and the Security Officer are really the same entity. Of course, this means that Durandal will be there, and help (for a braod definition) Cortana with her rampancy.

Forward Unto Dawn couldn't have been damaged from the Ark's destabilization
But something far, far more sinister. Knowing the flaws of Atmospheric slipspace jumps, the Arbiter managed to pull out of the Ark's breaking apart just enough to properly execute light-speed travel. Things got suspicious when this new enemy is made out to be worse than any Flood gravemind amalgamation. In short something had to have collided in its path and redirecting Chief and Cortana towards Requiem.

The plot will be even more confusing than that of Marathon
Because that would be par for the course for these guys.

You know what, the reason your fighting the covenant is because
They were cut off from the rest and didn't get the message for a long time. So of course they will fight you in the campaign, they didn't know that Truth betrayed the Sangheili and Thel finding out th truth of Halo etc, etc.

For the whole Reclaimer Trilogy
While in the final Marathon game there was parallel universe travel, at some point in the Reclaimer trilogy there will be time travel. Chief will be the one to activate Alpha Halo and possibly the entire Array personally - this being based off Guilty Spark's lines waay back in the original Halo. After all, he could tell the difference between Reclaimers (as per Halo:The Flood, with the Marine in the library) but he still expressed confusion over why Chief specifically was hesitant - saying "you were with me every step of the way [last time]".

Cortana will "die" at some point in the new trilogy.
Because let's face it, the odds are not looking good for her so far.