Can I swap in a more modern engine/transmission combination to replace a 460/C-6?

It's A LOT of work but yes you can. Actually, you can put almost any power-train in your truck if you have the means. There will be a lot of adapting to do since the more modern power-trains have computer controls for the engine and transmission. There are some aftermarket fuel injection system that'll bolt straight on to your 460 that will improve MPG and performance but, face it, if you want to pull down a mountain - you end up paying for it in gasoline. A splitter for the final drive helps a lot - the old "over-and-under" gear box will give you better highway mileage. My '87 4x4 gets 9MPG on a good day. But my Mazda Protege gets 30+. Guess what I drive daily and play with on weekends?