I think they will explore Nathan Drake's perpetual selfishness. At always getting his friends involved in these adventures, knowing the risk of life and limb. Sully practically left Nathan alone in uncharted 2 after he saw how serious things were getting. And yet Nathan is dragging him back!
On top of that, the tone of the trailer to me is suggesting something happens, Sully is probably in some sense removed from the picture, and Nate is either out for revenge or to save him.
I'd like if they explored Nathan Drake's extreme insensitivity to those around him when he gets obsessed with some treasure.