I think I remember this disussed before.
By talking with Pharo I assume here about another program talking to Pharo ? Possible not wrriten in Pharo ?
If thats the case then you can use whatever IPC works better for your needs. If the communication will be remotely I recommend sockets, for fast local communication I recommend shared memory. They are both very mature technologies , very reliable and cross platform.
Now on the URI protocol, I think that will depend what you want to achieve. Any string will be easy to parse with Pharo's regex and trigger the approriate methods. Pharo also have Annoucements, think of it as an event system that awaits to be triggered by an event, usually a Pharo event but I see no reason why it cant listen to external events either.
I do not think you will need a middle application , a servel client relation shipe should be more than enough.
With my Atlas bridge which is a Pharo library that allows you to use Python libraries I did a neat trick with Pharo that it already communicated with Python via sockets, sending python commands but also Python could communicate back errors , then Pharo would trigger the debugger, display the python error inside the Pharo debugger and the debugger would pop up on the exact pharo command that send the faulty python code. You could then change the pharo command on the spot and it was resent and python continued like the error never happened to retain the all important live coding workflow.
I created a tiny protocol to difirentia incoming messages talking about errors from the ones returning python varriable values. Something stupid like "pythonError: blah blah" but it got the job done