For example, Runners are weak and fast while Soakers have large health pools and travel slowly. The different enemy types have varying travel speeds, hit points, and resistances. To aid the player in this, information about upcoming waves is shown in the pause menu, as well as descriptions of the various enemies, towers, and weapons. Because certain towers are more effective against certain enemies, and only a select few towers affect flying enemies, the player must plan for all possibilities when building defenses. There are ten types of enemies in the game, three of which are air-borne.

Touching enemies will result in the player being knocked back, but no damage is done. Unlike most tower defense games, the player is allowed to move about the level during this phase and attack enemies with different weapon types, much like in a typical first-person shooter. With each enemy that reaches the core, the condition of the core degrades from 100% when the condition reaches 0%, the game ends. In the extermination phase, a wave of one or more enemy types moves across the level towards the core. Building and upgrading both cost points, which are gained when enemies are killed. The player can also upgrade any of the three weapons equipped at the start.

These towers include stationary weapons, teleporters for the player's use, and pads that affect enemies moving over them. In the building phase, the player builds structures on a pre-defined grid, using the eight 'towers' chosen at the start of the level. The gameplay in Sanctum is divided into the building phase and the extermination phase.

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