I took this from a youtube comment but a Hitman game where you have to assassinate Kane and Lynch. Actually, let's elaborate the target list a little so that I contribute something semi-original:
Lara Croft
Jar Jar Binks (47 is sent into another galaxy back in time, speaking of which
Young Anakin Skywalker
George Lucas (47 is sent back in time to kill him after making the original trilogy; sidequests: destroy all footage of the holiday special, seduce Carrie Fisher)
Justin Bieber (at Paris Hilton's party, miss Hilton is an optional target)
Michael Atkinson (would turn out to be a future dictator of a totalitarian Astralia and would start WW3)
Adolf Hitler (another timetravel; oh come on, if they can clone a supersoldier they can also travel back in time alright)
Solid Snake (fans of the MGS series will have the option to assassinate Sam Fisher instead; if fan of both series the player can suck a dick)
The Borgia family (another time travel; sidequest: paint the walls of your victims' room with their blood and write "See Ezio this is how a real assassin does it. P.S. Desmond is watching your bum and having an erection")
SHODAN (time travel to the future and having a hard time figuring out just how the fuck he should kill that slut)
Timothy Oliphant (the final boss of the game)
Another crossover world would be that of Final Fantasy XIII and Postal. You are allowed to take sides, guess which one is better.
EDIT - HOLY SHIT a superb idea just hit me like a lightning. L.A. Noire with the main protagonist being agent Francis "York" Morgan.