It's often said that good science fiction is about taking an idea that is initially preposterous and playing it straight. For this reason Shadowrun should really work. The idea is as preposterous as you can get and therefore, you would assume, has the potential to be genuinely interesting if taken seriously. (I don't mean being played seriously in-game; I just mean the actual setting itself.)
Unfortunately it always came across to me as being cartoonish and frivolous, as if the designers knew, in their hearts of hearts, that what they were coming up with was really rather silly indeed - or else a rather cynical attempt to gain popularity through combining two contemporaneous fads (epic fantasy and cyberpunk). Then again, my perception of the game may have been skewed by the gaming group I was in when I was 15 and Shadowrun was at the height of its popularity - the main raison d'etre for the group was actually smoking weed, if anything, which as well as robbing you of your ambition does not generally make for good gaming. (Don't do drugs, kids.)
I think the most interesting take on Shadowrun would be to make it more fairy-tale and supernatural. It's the future, we all have BlackBerrys in our heads and submachineguns which fire cyanide-tipped bullets and the Chinese and Brazilians have taken over the world, and yet at the same time...there are fucking elves around. And not your D&D "Legolas from the LOTR films" elves - your actual sidhe of myth and legend, who steal babies in the night and replace them with changelings, who trick you of your money and sanity just for laughs, or spirit you away for what seems like hours but actually turns out to be years. Or redcaps who lurk in dark alleys waiting to let your blood so they can dye their hats. Or Gibson-esque Voodou Loa who gain actual spiritual form from the worship of their immigrant followers. Or Wiccan gangsters who use magick.
The key to all this would be the interplay between the fairy and the technological, and the failure of high-tech to deal with the fact that there are more things in heaven and earth, Horatio, than are dreamt of in your philosophy. You know like how, in a cyberpunk game, the black ops wing of a sinister corporation could hack into your personal emails to find out your movements, or wait for you to come online and then fry your brain with hunter-killer software? Well, what would they do if you never came online because you use magick to communicate with your cronies? Wouldn't that sinister corporation want magick users itself?
Played straight, it works, see?