Basic issues that I can think of:
1. War with the Dark Matter Entities of Andromeda. This is the most straightforward, but also probably the one the Toughs have the least ability to actually affect due to the sheer scales involved. If nothing else, they're a small outfit best suited for "smash-and-grab" operations, even for all that they're operating a fleet now.
2. Side-effects of immortality. We already know of one past civilization that went for immortality (the creators of the amorphs), but ran into progressively greater limits that needed to be surpassed. Not the least of these, and likely the first humanity will reach, is the limits of the organic human brain. Even repurposing the skin and other organs at need only puts off the issue of a maximum capacity. Said past civilization solved this in two ways. The greater majority went for digital brain-uploading en masse, and wiped itself out in civil war. The minority went for intentional senescence, and survived to the present day; one joined the Toughs, left as part of a deal to save their lives in order to join the human Laz'r'us project under Auntie Emm, and...ah, ended unhappily.
...dissected offscreen for anatomical insights, and his death mentioned in passing. Since the Toughs memories of his departure were erased as part of the deal and very likely not recovered during the reconstruction efforts, they probably have no idea they should be asking questions, and the people responsible are all dead and thus unable to answer, so that at least is one side thread that's not going anywhere.
The only other immortals we are aware of are the amorphs themselves and the Oafans, but the former bypassed most of those limits by being originally designed as memory storage units and by having a high mortality rate for other reasons, and the latter...we're not so sure, but given their mature status, they seem to have worked out the kinks and were more than willing to help the humans along as well. I suspect that they'll do the same should any future issues arise due to human-specific biology as well, so this as a whole may not actually go any further...unless we run into an issue that both humans and Oafans can't fix...
3. The Great Filter. This one's been hinted at here and there. Heavy futuretech, but it's also something we know next to nothing about. To wit, the only known species (the Oafa) to have crossed it is one that effectively killed itself off via brain uploading in the hope that at some distant future, they would be revived. To say it's the Pa'anuri alone may well end up being too simplistic. What we suspect to be a war was fought over what this species left behind, but I don't think entities made of dark matter would have particular interest in Oafan tech; that in turn suggests that this war was fought by regular baryonic life forms with motivation to plunder Oafan installations and the ability to throw stars around on a sufficient basis to consider it a military tactic. Petey worries that the only candidate for such a thorough and effective extinction event is something like himself - to wit, the Fleetmind, but that's only hypothesis backed up only by very limited contact with a very unreliable...biological/cybernetic thingie termed an "archive".
4. What the heck the aquatic Schuul are playing at. This one's not futuretech at all, I suspect, but even nastier: political. It's also barely come up since the Massively Parallel stories (where their agent was working on setting off civil unrest), but it's implied they were the hidden force Petey was working against in the reality show media attack and, if their tactics in Massively Parallel are sound, the recent threatened civil war as well (given the aquatic nature of the dreamscape that was stimulated by the nannies that subverted the police, Mako included, which we readers only know about because she threw it off and the human government, I believe, doesn't know about because she didn't even know about the possibility of a Schuul threat to recognize the significance before she died). If the Schuul perceived humans as a threat before, imagine how worried they must be now that humans are both immortal and in possession of the technology and friendship with a precursor species that figuratively ate stars for spare parts. They might just pull in their horns and hope for the best while there's no evidence or even rumour implicating them, but I wouldn't place any bets on that.
5. ...there were other things, but my head hurts, it's late, and I forgot them. Sorry.