Cyberpunk is already a mash-up of hardboiled fiction and science fiction. Fantasy and hardboiled both combine well with science fiction on their own, but trying to combine fantasy with hardboiled without seeming frivolous or banal is a major undertaking in itself. Throw in s.f. as well and you've got a major oversaturation of themes going on.
This got me thinking: perhaps John is right, and mashing up two themes works fine, but adding a third causes the edifice to collapse under its own weight? Are there any famous or successful three-way, or four-way, genre mashups?
An experiment. Roll 3d10 and mashup the genres in this table. What do you get?
2, 7, 3: Noir, gothic horror, hard SF. There's a female vampire disguised on a space ship and gradually killing off the crew, and there's a whiskey-soaked detective on board who is in love with her and trying to solve the crime at the same time; the way he solves the mystery is through application of a clever scientific theory. Yeah, I can see how that wouldn't work - gothic horror and hard SF cancel each other out; if the vampire is really supernatural it isn't hard SF any more, but if there is a scientific solution then it isn't actually really gothic horror. Though both work well with noir.
10, 2, 3: Victoriana, noir, hard SF. A steampunk setting in which the details are meticulously laid out so that every element of the steam-powered world makes perfect sense. A whiskey-soaked detective attempts to solve a murder, but the solution revolves around understanding something specifically to do with steam engines. That kind of works, actually, though I'm taking a very loose definition of "hard SF". You'd have to really like steam engines, and really understand what they're capable of and what the implications would be.
10, 9, 6: Victoriana, literary fiction, western. A steampunk western in which nobody does anything except mope and ponder the imponderables while having ennui-inducing sex and taking mild intoxicants. Could sort of work if the writer made great play of the fact that steam, social conservatism and violence are sort of like the human condition. But would be boring and wasteful of its setting.
Maybe John is onto something.