Could you indulge me in some examples of things where the setting and mechanics are intertwined? Im not a PF2 expert but nothing I saw really looked difficult to ignore or explain away easily in any homebrew setting.
Sure.
Some background - I've been running this campaign for close to 2 years now, and am a subscriber to Paizo's "Core Rules" (meaning I get the books that are ostensibly setting-free). The homebrew is a pseudo-European Iron Age/Late Roman area, with a Romanized France fighting a Grecian Spain across the Pyrenees. I've also bought a few "Lost Omens" books for some choice bits. Example "Lost Omens: Character Guide" (alt-ancestries) and "Lost Omens: Grand Bazaar" (Loooot!).
I should also be clear the the core mechanics aren't setting dependent - the Jump rules, for instance, don't depend on Golarion in any manner. But that's not what I'm concerned about. What I'm concerned about is how much of the setting I have to scrub from the rules to match mine. As I completely made up example, if the spell description for "Finger of Death" references Pharasma(?) when my god of death is named Fuzzy Lumpkins, that's a bit awkward.
Where this most readily appears is in items. "Hellknight Half-Plate" is in the "Treasure Vault". Which should be setting-free, for the sake of argument. But its description explictly references that one villain country in Golarion that's ruled by devils. Now, it's easily corrected to a description of gear for a low-level fiendish minion, but that's a detail I didn't need to worry about, and now I do. Another example is all the gunpowder items, which I can just forbid as default. Again, though, a decision I had to make that I might not have needed to otherwise. These decisions and adaptions are usually quick and easy, but there are a LOT of them.
The next most apparent are the feats, especially the dedication feats, but every kind of feat can pose this problem. These usually require more extensive adapation.
Spells are usually problem-free.
I haven't even
tried to run any of the Adventures/Adventure Paths as those are so tightly bound to the setting that I'd basically be re-writing them if I tried to include them.
Now, I do not begrudge Paizo their effort in Golarion. It's a very solid setting, well-described, and well-fleshed-out. But it's also not one that appeals to me for various reasons that aren't germane to this discussion.
Keep in mind, I don't necessarily regard this as exceptional effort, but I also know I have a much higher tolerance for this kind of thing than many. I'll also point out that I had an easier time to adapt "Magic of Faerun" to my vanilla, but otherwise very non-Faerun, game in my 3.x campaign.