Cities: Skylines

I'm a longtime CS1 player. I use highways at times. Mostly for the grade separation aspect. I rarely feel the need to go above 2 through lanes each direction and 1-2 auxiliary lanes. Often I place 2 lane rural roads from the highway tab when I start building and leave land to preserve highway and rail corridors and upgrade them into freeways later. Don't be afraid to leave too much land along a road you intend to upgrade as you can always add infill development later. I usually leave at least 20u in width when I first plop one down. Use the query tool on the segments where the highway meets other roads to determine where traffic is trying to go. Using fully grade separated, free moving designs then running a little highway spur for a few blocks, or even a 2+1 road helps with collecting and distributing traffic instead of having a giant stack interchange dumping right onto a 4 lane avenue with frequent lights. If you play with despawning off, signalized freeway exits can be nightmarish and often necessitate the use of timed traffic lights and significant lane math and movement restrictions.

Lastly, your industry should have a clear shot to the highway, maybe even designated truck lane(s). If all your trucks have to pass through an urban area with lights and peds to get to the freeway, you're gonna have a bad time.

Hope some of this helps and I look forward to hearing other folks commentary. Good question.