Full story
Four years have passed since Doctor Strange's spell wiped Peter Parker from everyone's memory. Peter lives alone, gets by however he can, and spends his days and nights as Spider-Man with nobody to share the load. He avoids MJ and Ned on purpose, so he won't drag them back into danger. Giving everything to the suit leaves his personal life in pieces.
A telepath starts possessing people to stage prison breaks and break into Department of Damage Control sites, always hunting for something called V-Max. At the same time, Peter's body starts changing without warning. His eyes go black, his senses sharpen, and he begins shooting webs straight out of his wrists. The first time he faces the telepath, Peter can't control the new powers and loses.
The telepath is Jean Grey, a young mutant searching for her sister, Sara. Both of them were taken by the department, and Jean uses her powers to take over other people's bodies and create psionic fields. When MJ and Ned come home from MIT and Peter tries to reconnect, Jean turns that against him and nearly kills MJ. Scared of his own mutation, Peter goes to Bruce Banner, who helps him build an inhibitor to hold the changes back. Peter also learns that director Bill Metzger has been experimenting on people with powers, the Grey sisters included.
The final showdown happens at a department facility on Roosevelt Island. Jean finds out Sara died there. Consumed by rage, she creates a massive psionic field that freezes everyone except Peter. He rips off the inhibitor, accepts his new powers, and beats the Hand ninjas under Jean's control. Instead of fighting to the end, Peter lets Jean into his mind. There she sees a memory of Aunt May talking about unconditional love, and the two finally understand each other. Frank Castle, the Punisher, shows up and opens fire on Jean. Peter jumps in front of her and takes the bullets, and Jean is the one who keeps him alive.
Peter recovers in the hospital. Jean leaves the city, Metzger vanishes, and the department comes under investigation. At May's grave, Peter promises to stop fighting alone and finally introduces himself to Ned again. The rest of the rebuilding is left open. In the post-credits scene, Ned's Spider-Man tracking app picks up a sighting far from Earth, and that comes back later.