On Earth, the cardinal directions are straightforward. The arrow on a compass points to the nearest magnetic pole. You can then use it to travel anywhere on Earth.
In space, the idea of anything being “central” enough to be used as a “North” (since the universe has no center) or being fixated enough to not somehow pose issues is more convoluted.
If you were a pioneer of space exploration, what would your “North” be?
I was going to suggest the Great Attractor or the Shapley Supercluster, but I think your suggestion is better. It’s more point-like and since it’s farther away (well outside of the reachable universe) it results in a more uniform set of directions over long distances.
Of course, cultural influence will be big. If these explorers are Terragen then most likely the Milky Way’s north/south direction will be pretty deeply ingrained in their coordinate systems. They might keep on using that, since it’s not like manual astrolabe-style navigation will ever be relevant at that level of technology.