Players can interact with objects in the environment for the sake of background story rather than mere progression. Items are crafted from a pool of limited materials, forcing the player to decide which items are necessary. At any time, Joel can access his backpack to combine or use items, such as a Molotov cocktail or med-kit. The game also contains an inventory management and item combination system. Naughty Dog has coined their specific AI programming the ''Balance of Power'. Overall, the enemy AI is meant to be highly adaptable, reacting dynamically to how the player chooses to act. The humans are particularly competent: they can work together by relaying critical information to one another, fleeing, dynamically changing their tactics based upon whether Joel has a gun or a melee weapon, and surrendering.

Each enemy type has distinct AI patterns. The player is forced to contend against both the infected and other humans, although not every NPC they meet will be instantaneously hostile towards them. In addition, she will assist the player in solving certain puzzles and helping in situations which require two people. Ellie can die, but she will protect herself to some degree by using weapons and cunning to escape danger. Instead, Ellie acts as a supportive ally rather than a frail victim: she can call out enemies for Joel and help from afar by throwing objects at enemies. While cooperative play is absent from the game, Naughty Dog has stated that The Last of Us is not 'one big escort mission'. The player takes up the role of Joel, while their partner Ellie (computer-controlled) stays at Joel’s side for a large portion of the game. The AI-controlled Ellie preparing to throw a brick at a hunter The emphasis on player fragility helps accentuate the pressure of trying to survive in such a harsh world. Health doesn't regenerate, forcing the player to play very conservatively. While firearms can be procured, ammunition is incredibly scarce, making every bullet count. The weapons in the game are degradable, and the projectiles are mostly crude instruments such as bricks. The Last of Us ' combat primarily revolves around melee and crafting. There is speculation that the game takes place in the same universe as the Uncharted series, due to a hidden newspaper headline in Uncharted 3's first level that vaguely refers to a deadly fungus that scientists are still 'struggling to understand'. Supplies and ammunition are scarce and the player will have to constantly evaluate the risk of searching for these supplies in the environment and risking unwanted and taxing confrontations. The player takes the role of Joel (voiced by Troy Baker) and, with the help of 14-year-old orphan girl Ellie (voiced by Ashley Johnson), must try to survive at all costs, fending off both the infected and other desperate human survivors. The remaining survivors turn to whatever assets they can find to survive a world now overrun by anarchy and desolation. A large portion of the human race turns into monster, called the infected or clickers. The Last of Us is a third-person action-adventure game, set in a post-apocalyptic world where a deadly parasitic fungus ( Cordyceps unilateralis) that infects the brains of ants suddenly adapts to humans.

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