I'm about 12 issues into Hickman's Ultimate Spider-Man from 2024 and I feel like I could see some themes of this used in the MCU.
It starts by alluding to Tony Stark being gone. Peter was never bitten by the spider. An attack a year earlier killed May, Norman and Emily Osborn and long half the villains are leading different lives.
Oscorp, under Harry Osborn, acquired Stark/Stane and Harry becomes a hero that is Green Goblin using Stark tech, then meets Peter. It wouldn't be too hard to have this happen in the MCU since Stark is gone. They just explain Oscorp being created. Plus it doesn't interfere with Peter having already met and fought Norman Osborn and gives an introduction to Harry Osborn.
Also, Kingpin creates a Sinister Six of kinda random villains who run each of the boroughs, Mr. Negative, Kraven, Mysterio, Mole Man and Black Cat. While I don't think those specific characters would or should be used, I could see them leading to this with different gang leaders. Something like Tombstone, Hammerhead, Silvermane Mr. Negative, Kingpin and whoever is in charge of the Hand.
Just some thoughts I wanted to write down in case I'm right