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En este capítuloRodrigo Borgia, Pope Alexander VI, is poisoned.

Rodrigo's death leaves Cesare as the leader. He expands his army and threatens other cities. Ezio and the Brotherhood hit his captains and supply lines. After a series of defeats, Cesare retreats from Rome. The Assassins gain momentum, but the war is not over. Rodrigo's death is a major moment, since he was the main villain of AC II. His son proves to be a more ruthless leader.

The Brotherhood's strategy is a guerrilla war, using stealth and local support. It contrasts with Cesare's military approach. Cesare's retreat is a victory but also a setback; he is still dangerous.

En este capítuloEzio follows Cesare to Spain and retrieves the Apple of Eden.

Ezio pursues Cesare across Italy and Spain, finally recovering the Apple. Cesare is defeated and killed. Ezio takes the Apple back to Rome and hides it in a vault beneath the Colosseum. The Brotherhood is restored. The hunt for Cesare is a classic revenge arc with a twist: Ezio's goal is no longer vengeance but to protect the Apple.

Hiding the Apple in the Colosseum is a symbolic act: a Piece of Eden concealed in the heart of Rome. The Brotherhood's restoration shows that Ezio's leadership has created a legacy.

En este capítuloDesmond and the team go to Monteriggioni's ruins to find the Apple in the Colosseum.

In the present, the team follows the clues from Ezio's memories to the Colosseum, where the Apple is hidden. Lucy reveals that she has been working for the Templars. Juno, a First Civilization entity, takes control of Desmond and forces him to stab Lucy. Afterward, Desmond collapses into a coma.

The twist about Lucy is a shock to the audience. Her kindness was a mask, and her death is both a punishment and a tragedy. Juno's appearance introduces the series' secret antagonist. She uses Desmond as a tool, and the story becomes about control of free will. The coma sets up Revelations, in which Desmond must resolve his memories.