BEST UPGRADE regardless of cost?

The best upgrade is a balanced one, preferably the one that addresses the weakest links in your system. Short of that, it's like asking the question : Do you prefer to listen to a signal from a superb source that has been compromised by downstream components (including AC hash and room acoustics) or do you prefer to listen to the output of superb speakers that has been compromised by upstream components (and AC hash and room acoustics)? If the system is already fairly well balanced and you want to take it to the next level, I would agree with Warrenh: improve the source first. After that, it would depend on what the new and higher resolution uncovers. Experiment. If a weakest link is revealed, address it. If all the remaining elements are equally "weak" relative to the new source, upgrade the speakers next. There are no easy universal answers, unless you win the lottery...but then again...

A reel to reel tape player.

;-)

For myself there may be two I'd consider best. First being the acoustic treatment/taming the listening room and second a change of speaker cable.
This may be strange but I removed a Transparent Ultra from the system and replaced it with a vintage Tara labs and never looked back. Whoever bought the Ultra here on agon got it for pennies and I hope it works for them, it did nothing for me.

@khrys. I think your blanket statement on other AC power products is incorrect.   You might enjoy learning about balanced power from Equitech. Maybe :)

Spectral Pre and amp with MIT cabling. Spectacular improvement over the other “so called” top level equipment I had. I’m forever greatful to the well known,well respected Michael Percy (Audio) for his knowledgeable guidance. (PS for those unaware; both Spectral and MIT have extraordinary engineering talent whose expertise is respected by those in other fields :).