If you're talking about using the game to mirror real-life issues, then a sensible starting point is the idea that the corporations have already won.  Global capitalism is the standard, there's no point being a rebel or fighting the system because no-one cares.  The game should be based around the simple premise of "what's in it for me?"  In the old game characters had the choice between nihilistic anarchy and well-intentioned chaos; instead you could play on the difference between cold-hearted self-interest and a sense of enlightened self-interest - only treading on the people who really deserve it to get to the top.

I'd also probably get rid of the 80s-inspired consumerism where everything is disposable.  Increasing levels of environmental tax would mean that people would be more likely to have a few, very durable, very sophisticated pieces of equipment rather than a stockpile of guns and computers falling out of their pockets. 

At the other end of the spectrum, though, the bits that are disposable are very cheap and environmentally friendly - molecular computers integrated into sheets of paper that dissolve in rainwater, plastic packaging that breaks up under UV etc.

Another point to play up would be the contrast between people having access to a global information network, and yet being paranoid about foreigners.  Increasing fuel shortages and a switch to renewable energy sources would mean that jet travel is out of reach of all except the most wealthy, and any other form of long-distance travel takes too long for anyone that's actually got to earn a living.  As a result the world starts becoming a bigger place and today's levels of xenophobia rise.

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And I shall dwell forever in the house of the Lord... *ping* ...fire in the hole.

Instead of leather biker jackets and spraypaint cans it would be nylon/kevlar composite BDUs and smartcards.

In the old game your character might buy a half-dozen Chinese knock-off AK47s and spread them around a couple of safe-houses with one in the boot of the car.  Instead you have one zero'd-in OICW with onboard computer targeting, neural interface, semi-autonomous tracking and genetic lock and you look after it very, very carefully.

As another point, I think religion would play much greater role.  One of the things that CP2020 didn't do very well - for understandable reasons - was address the racial tensions within America.  However, what's going to become more important in the next few decades is the huge lack of understanding between the Mulsim and western worlds.  What if the Christian right-wing were able to force America into becoming a Christian state?  Another possibility is a United Muslim States of Africa - something that would scare the living hell out of America, Europe and China. 

The thing about playing with religion as a theme is that the characters can't base their prejudices on something as easily identifiable as skin colour, further increasing the levels of paranoia.

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And I shall dwell forever in the house of the Lord... *ping* ...fire in the hole.

One way could be to have a "conjoining" subplot (I've taken the name from the conjoiners in Alastair Reynolds, but there's a lot of other SF working the concept). You have a group of cybered people link up and start becoming a kind of hive-mind (how tight or loose the hive is, is a tricky matter to get the phys-repping and sense of a player's free will right). Other people will be scared of it, and may fear it, or want to destroy it. How it expands is another matter - will people be forcibly converted, as it's clearly the best way to evolve, or is it volunteers only? Actually having the formation of the new style of consciousness occur in the campaign, and spread via player action, would be best. It would also lead to a shift in the game - it could well limit the campaign's run if the hive-mind wins, unless you've prepared an external threat for them once all minds are part of it.

Another idea would be having serious genetic modifications rather than cybertech. This would increase a sense of weirdness, having people with genes from many species inserted.

Oh, we so need to do Transhuman Space LRP.

No, you probably don't remember my character from the events I've been to.

  There was some discussion of this on this thread:

http://forums.rule7.co.uk/Topic7112-44-1.aspx

  I'd be quite surprised if the hive mind wound up dominating IC- mainly because while I'd be interested in playing part of a hive mind, I think I'd prefer not to play hive mind characters repeatedly.  If one unit of the hive mind dies, then IC you can bluster all you want about how the hive is stronger than any individual while the player starts a character doing something different, but if that happens repeatedly then it's very difficult for the hive mind to achieve dominance over the whole setting.

 I'd like to see someone try it, though- I think you're right, it could be very interesting.

  Just so long as it went slightly beyond the standard Beatrix Potter larp (this is the land of the Snake People, this is the land of the Cat People, etc etc).  Not that I have anything against Beatrix Potter larp, in its place- but I don't think it would really suit an SF game.