I was thinking of a simple mod which added a terrain that you can't build any important structures on (So no smelters or walls or radars or assemblers or gun turrets. e.c.t.). (NOTE: all the ores should be located on a build-able area so you can build miners)
You will still be able to walk on this terrain, and still be able to drive your car/tank and run rail lines and power poles over the top, but you just can't have your factory on it. (Wether you allow belts on it is questionable).
I would imagine that in particular maps this terrain would be the majority of the map and you had to find small pockets of areas where you can fit parts of your base (sort of like islands in a sea).
Quick though, the terrain could be flooded marshes, so you literally build on islands but the water is shallow enough to drive a car over.
Because of this Biters can still cross it and attack your base but you need to keep your outposts (or islands) secure. This also stops people from turret creeping biter bases since their bases will usually be located in the no-build areas. (or you could put them on the build areas and you have to clear them off before you expand). This also puts a space constraint on your factory since you can't just extent your system out indefinitely. Eventually you need to find another build able island.
You could have a big area at your starting location as your main base and just have ore outposts, or you can have it very segmented and put little parts of your base all over the place.
I would assume creating the new terrain type would not be too hard (An assumption that Is more of a hope), but I would suspect that integrating it into the random map generator to create nice islands would be complex.