Most of the things that real application code (ie. not something like debugger) can accomplish by modifying or event inspecting frame objects are going to depend on various things that are documented as CPython implementation details. Also JS runtime that supports some kind of debugger interface has to solve the same class of problems. And the most straightforward solution is not even that complex: you simply have to track when some kind of assumption gets broken and then fall back to interpretation or recompile the relevant code (the most complex part of that probably is converting the native stack frame back into interpreter stack frame, which you have to be able to do anyway in order to even expose it to user code for it to be able to modify it).

In fact I think that there are many relatively simple modifications that would make CPython significantly faster, but many such things conflict with each other in ways that make the resulting complexity not worth it.