I’ve been using 1 shift on thumb for a few years now (first on my ErgoDox, then on the Model01), with all other modifiers on the thumbs too - all OneShot. It takes some getting used to, and if you try to hold them, that will be awkward - don’t do that. You can chain oneshots, so Ctrl+Alt+Shift is perfectly possible without holding any of them: just press them in whatever order.
If I do need to hold, I usually double-tap to make it sticky, instead of holding. There are some very, very rare cases where I hold a oneshot key (usually shift), but that happens once in a blue moon.
For me, this has been working incredibly well. I’ve played with having at least one modifier on the home row, but couldn’t get used to it, and ended up mistyping a lot. I’ve tried long press, but that slowed me down a lot. So I’m sticking with one of each modifier on the thumbs for the foreseeable future.