I think Prime 2 is the best game in the series. Doing Prime 2 + Dishonored 2 + something cool, would make for a fantastic experience.
I don't know if I agree with some others that they should make a multiplayer element, as I worry that the campaign will already be too much to handle and multiplayer will just bloat the budget, making it too expensive. I don't think anyone will pick up Prime 4 just because it has a fantastic multiplayer mode. Do people pick up Naughty Dog games for multiplayer? They think it's a fantastic add on, but I don't think anyone actually does. Maybe Nintendo could figure out a way for the multiplayer to pay for itself, like those games, through DLC or microtransactions? I guess at that point it's worth it. Whatever is necessary to keep Metroid alive, at no expense of the single player.
Something I would love to see Nintendo do, would be to go all out on the morph ball. Give it as much functionality as they can and do interesting twists. An idea I had the other day was for them to remake the spider ball so it actually grows spider legs and could climb up walls. Maybe give it other transformations as well?
Also, Prime 2 showed Metroid can have a great story without messing with the series trademarks. Hopefully they flesh that out. I like people's idea of being hunted by the Federation and Sylux. Have Sylux take Dark Samus' role and the Federation be a new enemy type. Maybe have Far Cry/Breath of the Wild style camps that the player can ambush and get story related material? Not too sure about that idea, but it might work depending on the structure of the game. It could add to the sense of fear and isolation, or break it, if not done well. All that, plus a time manipulation device that allows you to go between the present and the past where the ancient civilization was thriving, as a ghost, would be mind blowing!