Most LSx engines benefit from better air flow and a tune. It is not uncommon to see a well tuned LS1 with headers and LS6 intake only gain a couple (1-3) MPGs over stock, assuming the driver can keep their foot out of it.
Another area to address is the rear gears. 4.10s are crap for MPGs, so you could look into a gear swap to 3.73s or even 3.42s. That would help quite a bit for highway MPGs. It would cause a larger drop to towing MPGs though, as you're losing the low end grunt the 4.10s provide.
The most radical option is to upgrade the transmission to the 6L80E. I know it is pricey, especially if it only nets you another 1-3 MPGs, but combine that with the air flow mods and a good tune, and I wouldn't see it impossible to bump those things up to about 23 MPG highway (depending on your driving habits). I've read a few people who have done this on a TBSS and it was good for 2-3 MPGs on average. Still a big price tag for the minimal savings in fuel costs (truck still got only 20 MPG highway and the conversion cost about $5-6K).
