The three biggest boosts to my mileage were cruise control, a couple tanks of gas treated with injector cleaner, and tire pressure/tire type.
I was surprised at just how much better mileage I can get setting my cruise control and leaving it alone. People around here drive like morons. 85mph in the left lane, 60mph in the right. I get better mileage sticking it to 75/80 mph and doing short bursts to mesh with traffic to pass than I would driving a lower speed and having to constantly alter my speed to mesh with traffic or recover after needing to slow down behind slow traffic. Im not too thrilled about it, i would get a bit better mileage going 70 the whole way if i could stick it on cruise control, but the gas math favors the ability to do constant speed. I try to let it coast where I can, this thing doesn't slow down much unless you make it.
Fuel injector additive can work depending on how dirty your engine is. It can potentially give significant fuel savings off the bat if your engine has never had it done. In my case, it was about a 0.4 mpg increase after two tanks (~80 gallons) of fuel mixed with amsoil PI, but techron, seafoam, and lucas injector cleaners work on the same principals. Like 2smokin' suggested, cleaning the intake out more directly with seafoam can speed this up significantly if done right. It will help rid thei ntake of carbon deposits around the valves.
lastly, your tire size, pressure, and tread type all play a role in fuel economy. The dealer underinflated my new set of snow tires. (40 psi). I was getting roughly 0.5mpg less compared to my A/T tires that came with the truck. After going back to have it corrected, I saw roughly a 1.2 mpg increase overall. (60-80psi is typical, I told them to go 80 for tire rotation purposes, my compressor doesn't do above 45 well at this size. ) My snow tires, which are blizzak LT's are highway profiled. Despite being softer, they have less rolling resistance in the winter than your typical blocky all terrain tires and therefore can increase MPG. Personally, as someone that doesn't go off the road much, ill be going to a standard highway all season once these a/t's are done with. God those blizzaks were so much quieter. Keep in mind, when a 2500 is getting ~10-11 mpg, every additional mpg is a substantial increase. Right now, I'm averaging 11.0 mpg (calculated), and my best in the summer thus far has been 12.2 (calculated) and my best in winter was just shy of 13mpg. I do 90% highway driving.
Beyond this, the only possible increases in mpg is to make the truck more efficient. You would need to look a second gen for the 6 speed and notorious VVT along with the streamlined form. In general, doing the opposite of whatever you'd do for offroading is basically the goal for making vehicles more efficient. Lower stance, lighter weight components, lower gear ratios, eliminating the leech and weight of the 4wd system, thinner highway tires, reduce displacement in favor of better power-to-weight ratio choices, ect. And realistically, most of those things are a must the way they are for most owners.