Sure, but though I'm not that familiar with CPython and pypy, I don't think there are many situations where those runtimes have as varying and sometimes conflic

Sure, but though I'm not that familiar with CPython and pypy, I don't think there are many situations where those runtimes have as varying and sometimes conflicting requirements as Node and the browser. I'd guess the differences are more similar to the differences among the different browsers alone, which already are different runtimes by themselves. That said, even if those runtimes are as different as Node and the browser are, it's the interplay of that restriction in combination with the other characteristics I mentioned that make this a new challenge in its own right.