> There is a tiny bit of a backwards compatibility concern as the new function signature would be incompatible with anything we had before,

Right. If you call directly PyCFunction functions, you will likely get quickly a crash. But... who call directly PyCFunction functions? Why not using the 30+ functions to call functions?

Hopefully, it's easy to support METH_FASTCALL in an existing function getting a tuple:

   int nargs = (int)PyTuple_GET_SIZE(args);
   PyObject **stack = &PyTuple_GETITEM(args, 0);
   result = func(self, stack, nargs, kwargs);

I guess that Cython calls directly PyCFunction. cpyext module of PyPy probably too. Ok, except of them, are you aware of other projects doing that?