For Natural Selection 2, it was mainly the gameplay logic that was Lua, all running on their bespoke C++ game engine called Spark. But yeah, modern Python and Lua can be pushed to high performance.
Ah my mistake - I know they ditched Source to pursue their own engine and thought they were going all in on Lua, but doing the whole engine in Lua would have been a struggle I think.
Probably doable - I remember most of Natural Selection 2 was Lua and it's more than a decade old at this point.