Sequential fuel injection reduces the variation between the cylinders, with a ballpark fuel economy improvement of 8% just with that mod.

Running a “lean” air to fuel ratio of 20 to 1 dependably improves fuel economy by 25% compared to 14.7, but without sequential fuel injection to keep all cylinders even when running very lean the worst 3 to 4 cylinders will begin misfiring.

How lean can you go?
The Australian sold Honda Insight with one sparkplug per cylinder leaned out to 25 to 1 at highway cruise.

If you have a big cubic inch engine like a 440 and you want it to get nearer the highway fuel economy of a 318
you can get partway there by slowing down the RPM at highway cruise by the usual tricks:
2.76 versus 3.23 diff gears,
Gear Venders overdrive,
taller tires,
transmission with 0.5 top gear, etc.

If you get the manifold vacuum at highway cruise to 6 inches of mercury on both the 440 and 318 fuel will be converted to power at about the same.
Smaller cube engines have no “magic” .
Big cube and small cube V8 follow the same laws.

Is the engine size the only “ticket” to better fuel economy?

No.

Switching to newer design “low rolling resistance” tires is the fastest and easiest single mod.

Aerodynamic tweaks of the truck body can be achieved at surprisingly low cost,
and a D100 is way worse shape than any modern truck,
but a D100 has a smaller “frontal area” and lighter weight.

The 440 does suffer from its
high piston ring friction,
lack of “squish & tumble” in the combustion chamber design, and
slightly lower compression ratio,
compared to the Magnum 5.2 V8 under swap consideration.

A 5.7 Hemi with its twin sparkplugs and other tweaks is officially 6% better than a Magnum 5.9 V8, according to Chrysler.