[1][2] Sanctum 2 takes place in the future on the planet Loek-III where a major human colony has been established by the Britech Foundation in the city of Elysion-1, a vast elegant metropolis.

A previous arboreal settlement, Brightholme, had been set up in the wilderness but had collapsed from repeated attacks by the Lumes, a race of diverse creatures native to the planet.

It is hinted that some settlers still survive in the ruins of Brightholme and are part of an obscure organisation known as Tsygan, which is opposed to the vast, almost governmental power that Britech holds.

They convert inert gases like nitrogen into oxygen, and cleanse areas of toxic mushroom-like spores native to Loek-III, which are linked to Lume activity.

The team then regroups to fend off Lume attacks at various strategic locations, including a hotel park, a research lab, and the facility's main entrance, culminating in the defeat of a powerful boss, the Walker Patriarch.