I think it sounds awesome. It's almost like a combination of Far Harbor and Point Lookout, which are probably my two favorite things in the Bethesda Fallout games. Could also feature some Native American villages along the coast that are continuing their whaling and fishing traditions and connected by water, perhaps trading whale and fish oil and for guns.

As far as the central conflict goes, you could probably go with a New Vegas style power struggle over Portland (stay independent, join the NCR, join Cascadia), with both peaceful and violent paths. In the peaceful paths, the societies coexist and prosper, while in the violent ones the NCR is either driven from the Northwest or conquers Portland but can proceed no further due to Cascadia's command of the sea and the impossibility of a land invasion. Maybe whatever happened in Victoria was the result of covert action by both sides intersecting with catastrophic consequences, and you could present the evidence as either an act of war or a demonstration of how the destructiveness of a future conflict would leave no winners.

I've also been kicking around an idea for a remnant of the Unity made up of fanatical Children of the Cathedral believers and Nightkin fleeing North from the Brotherhood, who dispatch an expeditionary force to hunt them down. The Unity remnant has a sample of FEV and is looking for a bioweapons lab to create more and eventually recreate the Master, which the Brotherhood knows this, so the BEF will stop at nothing to wipe them out to the last mutant. Don't know how well that would fit in to what you have already, though. Maybe you could factor into what happened to Victoria?