Those examples are interesting because they show that Iso-8 isn't just a feature of some "Marvel Video Game Universe". Thor: The Dark World is technically part of the MCU and Spider-Man Unlimited is a multiversal game that ties into Spider-Verse, showing that Iso-8 exists across realities. This makes it easy, then, to have it show up in the OG Earth-616 Marvel Universe...which it did.
Blue Marvel was seen studying Iso-8 in The Ultimates #1 (November 2015), where he put forth an interesting theory: Iso-8 is a "cosmic counter", meaning that it's in its eighth iteration because the Marvel multiverse is in ITS eighth iteration.
I will say that it's POSSIBLE Iso-8's first in-continuity appearance was in Contest of Champions, a video game tie-in series that is itself in continuity. That would make sense but I can't confirm it. I can confirm, however, that Iso-8 will appear for sure in Contest of Champions #5 (February 2016).
If someone can confirm an appearance of Iso-8 in Contest of Champions before showing up in The Ultimates, please let me know.