The "immutable" thing shouldn't be a problem I'd think. Games installed through e.g. steam aren't affected by that — it just does its own thing creating a wine prefix for the game somewhere in your home directory. You should be free to do whatever you like in there.
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Games installed through e.g. steam aren't affected by that
I'm not worried about Skyrim not working, I'm worried about Mod Organizer 2 not working
MO2, in this situation, is just another Steam "game". You just add MO2 as a non-Steam game to your Steam library. Set your favourite Proton flavour as the compatibility tool for it, and then figure out how to configure the Proton prefix to make everything work.
Another possibility is to use Jackify to install a modlist for Skyrim. Will be easier, but costs one month's Nexus Mods Premium subscription. Jackify also supports flatpak versions of Steam.
Yeah by "do whatever you like" I mean install MO2, edit the registry, run dyndolod, mess around with system dlls, whatever. One thing I've just learned about that might be useful: https://github.com/SulfurNitride/NaK
No, it will not be a problem. I have modded gog skyrim version and all it needs is wine/proton.
I found a guide on setting up Bazzite for modded Skyrim. I don't know how accurate or up to date it is because I don't have Skyrim, but it's probably a good place to start.
Another option is Nobara. It's Fedora-based and gaming focused, while not being immutable. Additionally it's developed by Glorious Eggroll himself.