I think they'll leave L4D3 for the next engine.
I don't think putting in extremely random variation in the abilities of Common Infected is a really good thing, but more Uncommon Common like the Riot or the Clown Infected would be good. Maybe one like an infected that lost its legs but still moves extremely fast on the ground just using its arms. Obviously would be obscured by the standing hordes and could pose a minor inconvenience to the Survivors.
Anyway, what'd I like to see, in terms of gameplay are some more mechanics geared towards teamwork. I'm not saying stuff like crouching to give someone a boost.
But maybe something like if a Survivor is extremely low on health or incapacitated on the ground, another player could help him out, like, if, I dunno, one survivor's limping along in the teens in terms of health points, one survivor could help him over into a safer area, like, just help him stand with one arm, at the expense of only being able to use one pistol.
If the survivor's incapacitated, the other player could do like a Fireman's Carry, with the expense of neither player being able to use weapons.
Or at least just let people toss medkits to each other, like pills.
In terms of setting, maybe the Midwest or the West Coast would work nicely, but not cornfields or anything. Las Vegas would be neat to see, or maybe L.A..
Maybe expand on that whole Nick's Ring/Francis' Tattoo/whoever gets the design in Part 3 thing? Or make one of the Survivors a CEDA employee, see where that goes. Make one campaign about him/her goading the survivors to help him break into a lab or government building or something to steal samples or supplies or the like with the promise of an evac chopper.
Maybe send them through a zoo. The virus's been proven lethal to other animals but if it's mutated before, they can mutate again. Make some of the special infected in the zoo campaign animals. Gorillas or elephants for the Tank or Charger, a koala for the Jockey, etc.