In The Callisto Protocol, players assume the role of Jacob Lee, an inmate of Black Iron Prison on the moon Callisto. Jacob is controlled from a third-person perspective, and most important gameplay information is displayed via a holographic HUD viewed from the same perspective. Jacob's health is indicated by an implant on the back of his neck called a "Core Device", and his health can be replenished with injection-style pickups.

In addition to gun-based combat, there is a melee combat system in which Jacob must dodge enemy attacks while looking for openings to strike and kill the enemy. Enemies can lose their limbs during combat or be decapitated. If Jacob's health is reduced to zero, enemies will execute him in a graphically-violent manner.

In the course of the game, Jacob can also collect and review audio logs that provide deeper insights into the characters and setting. The Callisto Protocol will mix third-person combat with in-depth story telling. Providing the player with strategy segments and then expanding the story with around an hour's worth of cinematics that dive into the game's world.

Enemy variety will be expansive and will require a mix of ranged and melee combat to succeed. If the player utilizes all the tools at their disposal, they can complete the game in about 12-14 hours, and see the credits.

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