What I suspect they might do:
First off, definitely SPOILER ALERT** but if you're already on this topic, you are either stupid for coming here or have played through the campaign as I have already.
Well, for starters, Cortana's...ahem...appealing aesthetics definitely raked in some money for 343. Not saying that 343 are scumbag moneywh*res(looking at you Activision). But likely they will bring Cortana back. I just hope they don't give Chief a 'reincarnate' of her like she suggested.
Secondly, reiterating the initial few posts of her being turned and converted by The Librarian; it seems highly possible. Though I would imagine that 343, trying to change things up a bit, would probably leave her out for a game, and bring her back the next; as a sort of 'destined by fate' kind of thing. I like the idea of the data purge theory where she is sent to a forerunner database, and the Chief at some later point would have to retrieve her, and repeat the line he always says "You know me, when I make a promise, I keep it".
Thirdly, then again, it always is possible, she really is gone, though I would doubt ( AND REALLY HOPE NOT ) that they would do such a thing to all the hardcore Halo fans, who have been following the double C's all the way through the halo storyline; in summation, for a first game back, it would be really ****ty for 343 to do something like that to us. However, the thing that got me was, that when Cortana said "Don't make a girl a promise you know you can't keep" in Halo 2, she sounded slightly sure that Chief would pull through. In Halo 4, to me at least, she sounded despondent of hope when she repeated the quote, which might be 343's way of telling us that there was no way out of it.
Fingers Crossed, let's see what H5 has in store for us soon.