Comment by VorpalWay

Last I checked (a few years ago admittedly) Gnome Tweaks only configured the fontconfig setting, not the ini setting to make GTK4 programs care.

Also Gnome Tweaks is an add-on, not part of the default install on any Linux distro I have tried. In KDE Plasma this is in the standard settings.

And if you use any desktop environment other than GNOME, their preferences certainly won't set the GTK4 hidden ini setting. Rather they expect programs to follow best interoperability practises, such as respecting the fontconfig settings. Most people won't limit themselves to only first-party apps from their DE of choice, so interoperability is king.