Lost about 4 MPG highway somewhere

Made the yearly trip from SoCal to San Jose to visit family, outbound only so far. The two previous trips were something like 49 mpg and 48 mpg (according to the car). The path traveled is exactly the same each time, and the hours of the trip are also very close. This time the car was showing 45-46 mpg on stretches of road where it is normally 48-49 mpg. There was no headwind. Normally this is a one full tank trip, but it was burning enough gas that I added an extra 3 gallons at around 280 miles so I wouldn't be rolling in on fumes, or worse. The car showed 46.1 mpg when it reached SJ, which is of course optimistic. Total gas added for the trip was 8.4 gallons for 357 miles, or a real consumption of 42.5 mpg. (I know, I know, 8.4 gallons has big error bars from using 3 different gas pumps.) On previous trips the fills at the end were 7.5 and 7.6 gallons. (46.9 and 46.3 mpg, calculated.)

Temperature was about the same as the previous trips.

Traffic was perhaps a little lighter. I like to drive at 71 mpg on I5 using cruise control only (brakes are only used at rest stops, right?) So the average speed might have been a little higher.

Pulled the drums and checked the shoes before leaving and they were fine. Checked wheel temperatures at one stop and they were all just barely warm, with the left front a little warmer, which it has been since the bearing change.

Since the last trip literally all of the fluids have been changed, as have the tires. When the General Altimax RT45 tires went on I drove it for an hour out and an hour back on I210 and it was indistinguishable from the MPG with the previous Ecopias. It's possible that these tires have more rolling resistance as they wear.

I had noticed for a while that the highway MPG seemed a little lower than usual. Hard to quantitate with 10 miles here and 20 miles there. In suburban driving it isn't much different than long ago, except possibly that it takes a bit longer to warm up. Pre-trip had the wife drive and used Techstream to scan for codes (none) and check fuel trims and long term was, I don't recall exactly, but close enough to zero that it didn't suggest any issues. Short term was bouncing around with the driving conditions but never very far from zero either.

Car sounds normal other than a brief droning sound heard once and a while at very low speeds, no leaks, no smoke, no vibrations, no odors. It runs pretty much like it always did, but just doesn't do quite as well on the highway.

I'm thinking this might be either the injectors being a little dirty or the tires. Is it possible for the injector spray pattern to be lousy enough that it does not burn well, but the amount squirted in is normal, and it all burns eventually? Previous owner changed plugs about 50K ago, those should still be good, but maybe pull one to see if there are any signs of trouble.

I suppose there might be a tiny air bubble stuck somewhere in the ICE coolant loop from that change. I wouldn't expect that to affect just highway MPG though. Also the ICE coolant level has been completely stable since it was changed, and the amount in was incredibly close to the amount out (by weight), so it couldn't be too big a bubble.

Other thoughts?

Thanks.