My problem with making Cassie a protagonist is that is would directly go against what Nate and Elena wanted for their future, and by default, their daughter's future. Uncharted 4 is all about Nate going back into the game and he and Elena realizing they still have that itch, and Sam's gift of the treasure enabling them to have the means to do it the right way moving forward. In the epilogue we see that they've clearly been successful and have achieved some level of fame. It's everything Nate and Elena wanted - adventure and security.
Bringing Cassie back in obviously doesn't work if they're going to make everything done properly in the game. It won't have that same excitement in terms of gunplay, and from a storyline perspective, how do you end Nate's story and not expect him to be back in some role if the daughter is the main protagonist?
As I've said, I'm all for more Uncharted but it's gotta be Chloe in the lead, we already saw it works in Lost Legacy and between Sam, Charlie and Nadine there's enough legacy characters to have a full team but still make it feel fresh. They can stop numbering the games the way the Assassin's Creed games did after Black Flag to signal that they were moving on from Desmond and just give the games a name under a Chloe lead instead.
Giving Chloe a run of 2-3 games as the lead gives them time to wrap up Charlie and Nadine's storylines and give them an exit while introducing a new character to take over the franchise if they wish to keep it going. They can finish off Charlie in the first game, introduce the new lead in the second game and have them run with Chloe, Sam and Nadine while then finishing Nadine, and then the last game can give Chloe a good ending while then setting up the new character to take over with Sam sticking around in a Sully type role.
That would work much better to make sure these other characters had a chance to wrap their stories without Nate and Elena coming back. I don't want to see some nonsense happening to them after they got a happy ending.