Setting the system DPI to the higher res screen will only shift this problem to the other monitor as DOpus will then look blurry on the other monitor. I have tried and tested this.
I concede that Windows isn't all there with mixed DPI mode but the fact that there are more than a few programs out there that can handle it pretty well (they at least do not look blurry) tells me it is not impossible.
IME, it doesn't look (very) blurry when scaled down, only when scaled up. Maybe it depends on the monitors and resolutions, though.
It's not impossible, no. It is a huge amount of work with a program the size and complexity of Opus. High DPI support itself took about 6 months of work, and mixed DPI is harder in a lot of ways, because nothing can be cached and everything needs to be potentially reloaded and recalcualted at any moment. And every bitmap or icon or font that is displayed anywhere needs to know in advance which DPI it is being generated for (instead of being generated for the system DPI -- which may be high DPI but is always the same until the next restart -- and then usable on any screen).
I'm using a mixed DPI setup at the moment to find workarounds some issues, and also work on some completely new code (which is being designed for mixed DPI from the ground up, which is easier). Even with my own code working completely, there are so many bugs in Windows itself that I cannot understand why minor issues in Opus are something to complain about; the entire OS is unusable in this mode, IMO. (The standard File > Open dialogs don't even draw properly!)
We could certainly spend a long time adding full support for mixed DPI scaling and on-the-fly DPI switching, but anyone using Windows with that configuration would still have a miserable time due to the OS itself (and most other software), so it seems a bit pointless, given the amount of time it would take away from other work.
Any news on potential plans for mixed DPI support in Opus, even in stages?
I am a software developer and appreciate the work involved. However I've just done another review of most of the applications I have installed and support appears to be improving more quickly so I am hoping my high DPI monitor can soon join the others attached to my main development PC 
It may happen in the longer term, but not in the near future. It's a huge amount of work, and the OS itself is still intolerable in mixed mode, in my opinion.
Thanks for the update @Leo
I agree about the OS - on my latest check of the current state of play I found the least improved since my previous check was Windows itself.
Same problem here: using DOpus on secondary full HD display, while primary display is 4K. I do understand the amount of work involved to fix this. What you could do as a compromise is at least fix the main window (that is, the tree and the lister), which is, by far, used the most.
And the only real issue here is the font, you can leave the icon & bitmap code as it is.
bought a new 4k monitor (eizo, 27", 3820x2160) and have a second monitor (eizo 27", 2560x1440), which shows opus blury. when i postion the window with opus in the middle of the two screens (i have it expanded in win11), then the txt is much sharper (see pics). so how do i setup opus correctly, so i geht sharper text (the icons are ok).
Is it possible to manually increase the scaling? I experimented with your recommendations, but I'm stuck needing my lower resolution screen as the primary display. While a bit of blurriness is acceptable, I can't afford to have everything so tiny that it's unreadable. So, adjusting the scaling to around 150% or something similar would be incredibly helpful. I've already exhausted the available settings, including opting for larger icons. Despite my efforts, I've found no other solutions in forums, documentation, or even through Google searches.
If you set the secondary monitor to a higher scaling in Windows, anything displayed on it will be made larger automatically. (As long as the majority of the window is on that screen.)
