Lena’s ex-boyfriend, Jack Spheer, comes to National City to unveil his big breakthrough in nano-technology, which has the potential to eradicate all diseases. Lena asks Kara to attend Jack’s conference with her for support. When Kara sees Snapper in attendance she’s inspired to tap back into her reporter skills and questions Jack on his discovery, which ultimately leads to a bigger investigation that puts everyone in danger.

Supergirl learns the true depth of Serena's nefarious plans for Earth. Supergirl, Mon-El and Alura must devise a plan to stop her before Serena gets to Earth. J'onn prepares to say goodbye to his father.

When Supergirl needs help, Alex asks Lena and Brainiac to team up. Meanwhile, J’onn questions his decision to quit the DEO. However, after running into Manchester Black, he realizes there are a lot of ways to help his fellow aliens during this tumultuous time.

Nia’s roommate, Yvette, is attacked by a man targeting Dreamer because he doesn’t like that Dreamer is transgender and wants her to quit being a superhero. Determined to protect her community from additional harm, Dreamer refuses to give into his threats and puts herself in the line of fire to stop him. Supergirl stands by Dreamer and enlists additional help from Brainy. Meanwhile, Alex, J’onn and Kelly attempt to rescue a man stuck inside a virtual reality escape room.

As Supergirl and Zor-El make their return to National City, they are determined to keep the Phantom Zone behind them and enjoy being superheroes together. Unfortunately, their overzealous efforts backfire, creating a whole new threat to National City.