You guys haven't got any more clue than the idiots developing it.
What fallout should have done when it went 3D sandbox survival is ditch the fucking story completely. Start the player alone not knowing what the fuck is going on, and let them run into and find the story or stories in the world as they explore. The player character is nobody, the game shouldn't tell you anything about who you are, the only thing you'd have set in stone about your character is the location you start in. Everything else is imagined by the player.
If you want to streamline the skill system, combine skills with SPECIAL stats, not skills with perks. Then make it so that the lower your skill started at, the more points you have to spend to increase it later.
Quests should not exist as we know them. They'd technically be there, but you wouldn't ever "get a quest". If you talk to people, you may hear of a problem or something that needs to be doing and can ask more details about it, but it's up to you to pay attention about where it is and to go see yourself if there's anything you can do, if you want to do so. I honestly don't feel free to NOT do a quest when a big "QUEST STARTED HELP THESE POOR PEOPLE" appears on the screen and then that fucking quest clutters the quest list until the end of times unless I go and finish it (and all the other shitty quests that one leads into). It doesn't feel like my choice to do it.
Utilizing 3D could be a very interesting opportunity for something new. For instance one thing I've been thinking of is the ability to press buttons and pull levers in the world with your mouse. Then create some kind of mechanism where you need to press buttons and pull levers and balance some gauges or something in order to activate it. You could tinker with the machine literally at any time, but the actual instructions to correctly activate/operate it are hidden elsewhere in the world. It's like one of those "locks" in Zelda games where you need a special item to bypass an obstacle, but instead of an item, you need knowledge in your own head. You could use this idea even for repairing and operating power armor, there could be a special way to open the power suit in the first place, and if you don't know how to open the particular suit you found, you won't be able to pilot it. You could try and maybe open it by accident, or use a skill check to force it open. Just imagine how immersive and satisfying it would be to learn how to operate a device like that, instead of just "press A to use" or receiving a key every time. You could also have some kind of rpg mode where you must find the knowledge before you can operate the device, even if you already know it yourself.
Same could work for secrets. You could put a secret lair behind a bookcase right in front of the player's face, but unless the player knows it's there, they won't know to pull a book to open it. And don't show a "PRESS A TO PULL BOOK" when the player looks at the book, let alone the entire bookcase. Instead somewhere in the same building or the world, you tell exactly which book to pull in which bookshelf. And when you learn that, you don't get a map marker pointing at it, you'll just have to go and try it yourself.