Python (and calibre) when running under Windows uses the Windows system certificate store.
That can sometimes causes problems because that store is typically only updated when used. In most cases calibre root certificate problems can be corrected by opening Internet Explorer (or Edge) and navigating to the site that is experiencing problems.
However in this case when I tried it for a Let's Encrypt based site that was giving my plugin trouble at the end of September it still did not correct the problem. I was eventually able to get it working by removing an expired intermediate certificate from the Windows store. My assumption is that the presence of this certificate was causing python's SSL/TLS handling to fail. More details in
this post.