[I have not read @BrenBarn’s post, too long, sorry. But I hope it is fair to answer the question in the title anyway.]
One item on my wish list is interoperability between (packaging) ecosystems. For me this means interoperability between for example the (packaging) ecosystems of Python, Node.js, Rust, as well as system packaging ecosystems such as apt, yum, brew and so on.
When I see initiatives like PyBI, PEP 725, purl, and others, I can’t help but think what if I could npm install python Django or pip install nodejs reactjs? Wouldn’t it be great if pip could install gcc in order to build C extensions? Ideally there would be installers that work across ecosystems. I am tired of having things installed with pipx, others with conda, some with apt (I have managed to avoid brew and nix so far) and losing track of what should be updated when and where.