Before I say much else, my 'tuning' experience is limited to three cars, all fords, one supercharged 5.4 v8, one 4.6 v8, and one turbo 4.6.
I'll use the lightning as my case. Its is a supercharged and heavily modified 5.4 v8. Specifically regarding fuel delivery: even after upgrading to two 255#/hr pumps, adding a resistor to correct a hi/lo relay trip issue, upgrading to 60#/hr injectors, and higher capacity fuel rails I'm still using a high percentage of the overall fuel delivery capability at wide open throttle. This is using CA 91 octane which as I understand has a minimal but present ethanol blend. Because this is a hobby and coming out of my own pocket, I never run systems to 100% of capacity if I can avoid it.
Now from talking to other L owners and exploring an e85 conversion much over the last 10 years, here are some relevant points that stand out when talking of efficiency:
Switching to e85 for my application would at minimum require a retune and more upgrades. I would need bigger fuel pumps, stainless fuel lines, maybe bigger rails, and definitely 80#/hr injectors for this same power level.
Switching to e85 will net me worse gas mileage. If I'm lucky I can get 13-15mpg mixed city/hwy on CA 91. Similarly modified L's on e85 regularly report 15-25% worse fuel economy (or 7-10mpg to be specific from conversations and forum threads).
Switching to e85 also has a tuning/performance perk of having characteristics of a higher octane rating (to the note of 104 octane). On e85 I can potentially make more power, but I'd also have to dump substantially more fuel in each cylinder than I would have to put non ethanol gasoline to achieve the same power levels. At some point e85 beats CA91 for potential resistance to detonation.
Now real food for thought: I just moved this truck out of CA where I can put non ethanol 93 and 98 octane gasoline in the tank. The truck feels to have noticeably more torque across the entire rpm range (at a higher elevation to boot) and so far I've documented an average 17 mpg on the last tank mixed country road and small town driving. The best MPG I've ever seen in this vehicle was in 2006 driving through northern Texas, all freeway a freakish 20mpg that never happened again (and I do not know if this was plain gasoline or e blend, it has been awhile).
And finally one common overlooked part that all L e85 conversions must do: in the fuel tank the Y that connects the two fuel pumps to the fuel line is factory plastic. If you do not replace plastic fuel delivery components with stainless steel replacements, on e85 they will dry, crack, and fail. In my case this could mean a blown motor. Hence the need for stainless fuel lines, too.
I can only imagine an otherwise stock car on a stock tune not meant to run or not specifically tuned to handle ethanol or ethanol blends would feel to run more rich and get guaranteed worse fuel economy. My own research seems to indicate so.