I have a 2/50/2 as well as an older Matrix solidstate amp and have also used the FX return of other tube amps.
The 2/50/2 is great and certainly on the more neutral side for a tube amp. very good punch, but I prefer the matrix with the axe FX. Just less fiddly to get a good sound. With the 2/50/2 I’d prefer to turn off the power amp models and use the axe FX as preamp-only but not all models really pair well with the 2/50/2 as the power amp. It also imparts a certain ‘sameness’ to all the models since I am using the same power amp for them all.
I used to try to run full amp models into the 2/50/2, and that works for some, but not the majority. The ‘double power amp sound’ is not great, in my opinion
on the other end of the spectrum, I’ve run the axe FX into the FX return of my mesa dual rectifier and while it sounds huge and awesome, the rectifier poweramp is so coloured that everything basically just sounds and feels like a slightly different flavor rectifier.
i use real guitar cabs, never really got along with FRFR but I also haven’t tried anything nicer than some mid-tier PA stuff, and studio monitors.
I have an oversized Marshall 4x12 with V30’s, a home-made 2x12 with h75 creambacks, and a Zilla 2x12 with V30/K100 combo. All work great.