I can't name a required change because it's a fundamental change. This game has had 13 years of development and all of that would have to be redone with the new worldtype in mind.
I've already named the required changes.
Alright, then I'll try to name some difficult things.
1. Positional logic, especially as it relates to pathfinding, movement in general, fluid physics, combat, stockpiles, buildings... wait, I'm listing everything in the game.
2. Modding issues. Despite what you seem to think somehow, this would be significantly more difficult to mod for than the current system. Meshes are
difficult to work with. Numbers representing positions relative to some origin (as I assume you're referring to) are not really intuitive at all.
3. Visuals. Armok 1 is an uglier game than Armok 2. A mesh-based game would likely look far uglier than a tile-based game. Vaguely cat-like boxy things are harder to recognize as a cat than the letter 'c', simply because a vaguely cat-like boxy thing also looks like a vaguely dog-like boxy thing. The best way to mitigate this would be texturing, and there you go making it harder to mod again.
4. UI. Designations would become more complicated and switching to meshes won't magically make the rest of the UI any better; in fact, the likely lack of slice-based rendering makes the UI in general far worse than it currently is. That will have to be redesigned as well. Viewport isn't that big of a problem, actually.
5. Dimensions were already a fairly difficult problem. Meshes suggest an
exclusively privileged fourth dimension as opposed to, for example, one that can be traveled through at-will by certain agents or the player's viewport.
6. Looking in directions that aren't top-down would be silly when embarks are only a certain size.