In general, highly toxic, self replicating substance. Some kind of superweapon that contaminates infected planet tile by tile and kills/mutates inhabitants. When all tiles are infested, planet turns into toxic one. What about that? Player (human or AI) could develop that weapon (from Scourge remains?) to destroy enemy planets in galactic scale attrition warfare.
I actually thought this out myself.
Take a look:
Toxic phlebtonium isn't quite inseparably integral to the space opera genre, but its two most iconic examples; Phazon and Tiberium from Metroid and Command and Conquer are cool enough that I thought that something inspired by them could serve as the basis of a crisis.
The first inklings of the issue could start rather early in the game; perhaps midway through when you or someone else discovers a planet seeded with the substance through means of FTL meteor sent by the progenitor of the substance (let's say a living planet, the very first planet in the galaxy corrupted by the substance) some time ago. The substance has caused significant ecological disruption, turning wildlife exposed to it incredibly dangerous and hostile, but the substance itself has tremendous usage for well...everything. It's a power source that can put zero-point energy to shame, it can be used as a mutagen to create deadly super soldiers, and like Tiberium it can be easily used in nanolathes to create just about anything. However the more it's used the more it corrupts a planet, and both mechanical systems and life forms infused with it will also show signs of corruption with the occasional supersoldier becoming a berserk monstrosity.
However it's just so good that it's hard to not go farther with using it everywhere, spreading it across the empire(s) that discovered it and intensifying the level of corruption throughout the galaxy. Eventually you start getting things like Brotherhood of Nod esque cults dedicated to the substance that if not appeased through essentially giving them the keys to society will end up starting a civil war; or take over the empire entirely as the dominant faction if allowed to. This starts phase one of the crisis where the cult or corrupted empire tries to aggressively spread the substance to everyone whether they want it or not, pushing what they can do with the material to ever greater heights, though this makes everyone who rejects the corruption turn on the "carrier" civilization.
Phase two begins when some form of life form native to the progenitor world emerges and takes over all of or part of a civilization, creating another "carrier" civilization, though this one has greater control over the progenitor world itself to the point of being able to direct the planet's FTL meteors and controlling the corrupted life forms. Like the Vehement or Aberrant they are quite likely to be hostile to the cult, which wants to use the substance to launch some sort of ascension while the controller entity wants to use it to dominate the galaxy. If an espionage DLC is released before this, the controlling entity would be much more difficult for special forces/bounty hunter/spy teams to kill than the cult leader who would probably be a more Kane like being in that they rely mostly on charisma and genius rather than personal power to manage their cult if not nearly impossible (and quite possibly neither stays dead for too long when killed outside of the appropriate contexts like Kane and Dark Samus never seem to stay dead until all Phazon in the universe was destroyed for the latter and I'm pretty sure nobody's ever figured out a way to keep Kane dead).
The third phase comes when an extragalactic civilization heavily tied to the substance (to the point of being life forms based on it) determines that the galaxy is sufficiently seeded with the corruption to begin the harvest. This civilization is hostile to both the controller and the cult and cannot be meaningfully negotiated with, as the harvesters don't really care about whatever objections carbon/silicon based/synthetic life forms have to the Harvesters' operations. The harvesters of course focus on spreading and mining the substance and destroying any civilization that would try to interfere with the harvest.
Ending this long running crisis of course requires cutting the serpent off at the head, you must find some way to destroy the substance. To deal with the Cult (if you aren't yourself the cult), you have to thoroughly militarily crush them and ensure no POPs that are members of or are sympathetic to the cult have access to the substance. To deal with the controller you need to engage in a questline to find the progenitor planet after dealing with heavily corrupted seeder planets to launch an assault against the living planet and deal with the controller entity once and for all. To deal with the harvesters will require forcing your way through the primary threshold gate to launch a direct attack on the hub of their operations in a special solar system outside of the galaxy to persuade them to leave this galaxy alone, with your forces then high tailing it back to the galaxy before the harvesters can send in reinforcements to crush the intrusion in their home galaxy and before the gate back home closes and traps everyone you sent (which would be counted as losing all forces there as they're lost in another galaxy with no way home with retaliatory strikes on their way).
Attacking the harvester hub would be a challenge in and of itself as not only are there some doom stacks waiting there at all times (along with heavy fortifications around the hub) and fleets coming in from the rest of the harvesters' multi-galactic empire to get ready to transfer into our galaxy through one of their threshold gates, but the moment the Hub is attacked enemy reinforcements will continually pour in the longer the battle goes in to deal with the intrusion. So you really need to push through fast and hard and land a bunch of armies to destroy the hub before turning back. It's meant to be a bastard and a half of a battle to win as sort of a punishment for letting the levels of galactic corruption for getting this out of control. Luckily for you, once the hub is destroyed, said multi-galactic civilization decides your galaxy isn't worth the bother and leaves you alone since a war of attrition with a Type III civilization that controls more galaxies than you control planets when it cares to go into total war against you instead of just using harvester security fleets to protect their investments is a losing proposition every time.
In essence in a game with the corruptive substance, you are offered tremendous power at the cost of possibly damning the entire galaxy to madness and addiction to a poison that has an overpowering directive to spread; to twist life into degenerate mutants and turn whole worlds into radioactive hellpits consumed by the substance. And the people who spread the substance in the first place are going to be collecting the return on investment sooner or later. Meanwhile the Galaxy tears itself apart as some see the substance as merely a tool but the path to ascension and godhood, while others fall under the thrall of a malevolent predator born of the substance who wishes to dominate the whole galaxy with it. And unlike most other crises, you yourself could become part of the problem if you choose to surrender to the addiction rather than fight the substance.
The only thing I'm not sure on is what to call it without sounding totally dorky or obviously borrowing from Phazon or Tiberium's names. Exteritite (from one of the latin terms for corruption) mayhaps?