A previous storyline had already featured the other DC Comics icon Batman fighting the Predator, while Superman had also been shown battling the Aliens from the Alien film series. Most recently Batman and Superman have been shown battling both the Predators and the Aliens side by side.
A S.T.A.R. Labs expedition uncovers an ancient derelict spacecraft in the jungles of Central America. Superman investigates the ship and is afflicted by an alien virus causing his powers to fluctuate wildly. The group is captured by a band of mercenaries working for a clandestine scientist. He plans to use the alien technology to facilitate selective global genocide based on genetic sequencing, but he didn't count on one thing - the meanest alien hunter in the galaxy! The Predator senses Superman is a worthy opponent and begins stalking him while concurrently seeking to reclaim the stolen technology appropriated by the scientist. It's a race against time for Superman to save countless millions of lives.