Fallout 4 wish list:
1) Isometric/3rd person view combat
Isometric combat can still work. What they need to do is to offer three modes of combat - turn-based, paused-based and real time. The innovations possible here is to implement an intelligent cover system, in which enemies, allies and you yourself are able to take cover behind various stuff and even blind fire from those covers. Think of the perks that could aid to this combat style.
Of course, in turn-base the cover system would pretty much be hard to implement, but I'm sure with a little brainstorming it would work. D&D transited well from turn-based to pause-based right?
2) Completely destructible environment
You can blow up an entire town by rigging enough explosives around town. Or you can blow your way into a building by using some heavy machinery. Or just chip away the walls with a minigun. Or rocket launcher.
Destructible environments are nothing new, but having the ability to mow down a building would be bad ass in an RPG.
3) Everybody hates vault dwellers
Make the world so that nobody likes vault dwellers. Hey, they were the ones who shut the world out during the nuclear fallout, so why would anybody want to help any dude wearing a vault suit?
4) Fully rendered talking heads
Forget about in-game cut scenes. Bring back talking heads and give them full rendered sequences. This is what makes them memorable - the few key person in the game that stood out from the rest.
5) Epic plot
C'mon, creating pure water for people is a good story? How about something more epic, like the hero's vault being invaded in the beginning and having the hero escape the vault with only a holotape with a cryptic message. And then turns out that the only survivor of the vault, you, holds a valuable key that several major factions wants, only to find out in the end that this whole shebang was an elaborate conspiracy weaved by a hidden antagonist intending to play the factions against each other. Add a twist to the hidden antagonist being somebody the hero knows very well? That would create enough choices in the game (which faction you choose, how would you rally the wasteland to face the new threat) to make an RPG player drool for months.
6) No more mini-games
Mini games suck. If I want to play mini-games, I'd go play flash games. They have no place in an RPG and its just a complete waste of time. Let character skills and dice rolls determine everything.
7) Memorable NPCs
NPCs with history, hidden agendas and even manipulate and betray you in the middle of the game would rock. They should have individual personalities and being nice to them won't always work. Some would need you to use intimidating or seductive talk to improve their perception of the player while others just don't like assholes.
8) Innovative conversation system
Characters should have a "mood" system (Lynnet in Vault City is a good example) in which they would hold grundges to the player if he says the wrong thing. Punish the player for making certain choices. Forget about those crybabies and let players learn the ways of the wasteland THE HARD WAY.
9) Proper gore
Let me rip a super mutant in half with a minigun or tear off half a torso from a bandit with a well placed gauss rifle shot.
10) Ambiguous Morality
Punish the player for attempting to be a "good" guy. Make a town get massacred if the player helps the sheriff kill a gang leader (or exile the gang). Turns out this decision later would lead to the town getting waylaid by some random bandits and without the firepower of the gang, the town is laid to waste.
Or have the player help some poor ol' beggar only to be drugged and robbed of all his belongings.
Punish the player for being too "good" in a very naive way, and let the player know that sometimes in the wasteland, being badass is just a necessity for survival.