I think the big thing is connections:
- currently, you can spam 737F, A321F, 757PF, whatever, and kill the larger birds
- on the other hand, small and medium freighters are pretty much useless (while IRL they are very nice feeders, as Dani pointed out)
- some RL medium can carry even HC, which is not represented in the game (and I accept it in the current design)
However, once connections are enabled, hubs are also de facto enabled, and at this point medium will become useful, as the efficiency of one's hub might very well depend on these. On the other side of things, connections between large areas will be done by VL freighter (there might be some ankle bitter, sure, but at this point he wouldn't be as efficient as he is today).
But to achieve this in an interesting way, I think the hubs should have to ability to some extent to turn LC and SC in SC and HC respectively: thin routes have their interest, thick routes as well, and the concentration effect is also pictured, and the market is divided. And at this point, large freighters like the 757 or A321F are perfect to to point-to-point and compete with the hub system, but can't be used to turn an airport into a major cargo hub without the help of a network of small/medium freighters and would thus be limited to linking cargo-dense areas.