The following is my personal experience:
Used to be a livery driver / chauffeur in NYC / NJ / CT, usually driving a 2012 GMC Yukon XL with a 6L80E (started driving it in 2013, it had about 50,000 miles on it already).
I drove it for one year as GM spec'd it, then I had a brilliantly (dumb) idea:
INCREASE V4 mode's duty cycle, to improve the XL's metro / urban and highway MpGs.
Normally V4 mode operates in 5th and 6th gears, with very rare activations in 4th gear.
Had a custom tune written that not only increased V4 mode duty cycle in 4th 5th and 6th, it even allowed some V4 mode in 3rd.
(I could feel it, and hear it if I listened for it, but no one else noticed.)
Although I did save some fuel in the 1st year, fuel consumption increased in the 2nd year.
By the 3rd year, the MpG savings were no better than its original year with GM's OE V4 mode duty cycle.
In the 4th year, despite MONTHLY 0W30 or 5W30 synthetic oil changes (3000 miles or LESS every month), oil consumption became a problem.
My guess:
every time the On/Off cylinders turned off, they got colder than the always-ON cylinders and wore out a bit more quickly than the always-ON cylinders. (I was never able to confirm this theory; there are other possibilities.)
I put on about 40,000 miles every year.
Seems I changed the oil often enough to protect the lifters, but nonetheless could not prevent extra oil consumption.
As a direct result of my experience, on top of the excessive number of failures of other engines with cylinder deactivation,
I will ALWAYS enthusiastically recommend disabling V4 mode, whether by plug-in or by ecm tune.
If your engine still has cylinder deactivation mode (AFM or DFM, whatever), disable it already.