The same night, a group of criminals kill Travis's best friend, Bishop, and throw his head through Travis's window in a paper bag. The nearly-dead Skelter Helter interrupts them and warns Travis that he and his co-conspirators will still have their revenge.

After winning the battle, he meets Sylvia Christel, who informs him he is ranked as the 51st best assassin. He has returned to Santa Destroy and fights Skelter Helter, who seeks revenge on Travis for killing his older brother Helter Skelter prior to the first game. Three years have passed since Travis Touchdown became the top assassin in the United Assassins Association (UAA) and walked away. The story of No More Heroes 2 is told through cutscenes following Travis' journey, interspersed with scenes of a woman at a peep show dictating the story's events to an unknown observer. A port of the game was released for the Nintendo Switch in 2020, and for Amazon Luna and Windows via Steam in 2021. The game had scattered release dates across regions, being released in North America on January 26, 2010, in Australia on May 25, 2010, in Europe on May 28, 2010, and in Japan on October 21, 2010.

Upon discovering that the corporation's CEO placed a hit on his best friend, Travis rejoins the ranks to fight his way through an even greater number of assassins to confront his best friend's killer and attain revenge. The game continues the story of professional assassin Travis Touchdown in the wake of his warpath through the ranked assassin battles, his home town of Santa Destroy transformed into a hotbed of for-profit killing and murder entertainment, spurred on by a corporate franchise taking control of the city and commodifying assassins. Desperate Struggle was produced by Suda51, developed by Grasshopper Manufacture and published by Ubisoft, Rising Star Games, and Marvelous Entertainment. No More Heroes 2: Desperate Struggle is an action-adventure hack and slash video game developed for the Wii video game system, the sequel to 2007's No More Heroes.

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