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Profiling is the source of truth. Try setting up a scenario that exacerbates the issues you think are happening.

I've seen shaders cause problems due to branching logic- I'd try disabling them or making them perform a no-op.

I've focused on 2D with Godot, but often with a very high volume of nodes at once.

Of course. I use both the built in Godot profiler and perf.

Which led me to change many things in the implementation and I also ended up patching the Engine multiple times.

One example is this (which I have patched on my Godot version): https://github.com/godotengine/godot-proposals/issues/4050

I profile my game all the time, but sometimes it's not clear if there is a bottleneck or if there are just too many things at the same time.

Also the bottleneck can change in different parts of the game. Sometimes I have removed a bottleneck on the CPU just to find another in the GPU.