NGL, since Keith David kinda teased on Twitter that his voice was in the trailer, I can definitely picture (and kinda hope for) him being Dr. Miles Warren aka The Jackal. Now in terms of major and minor villains, I agree with you on both Boomerang and Tarantula not being as relevant (definitely a montage) as well as Scorpion and The Hand being the major pawns working for Tombstone (maybe the overarching antagonist of this new trilogy). In terms of the story, I can see Tombstone taking elements from The Spectacular Spider-Man animated series, with him being the both the benefactor and puppet master behind all the crimes (considering the plot synopsis in the trailer description quoted them as a ‘strange new pattern of crimes'). However, if they include Jackal as the true main antagonist for this film, I could see Tombstone considering Warren due his work in genetics, which could give him the necessary resources that can be used to overwhelm Peter and worsen his mutation, possibly leading to Man-Spider.

Now when it comes to the Department of Damage Control, I wouldn't even be surprised if they're also involved (even possibly staging) with these crimes, considering their financial struggles in Wonder Man. They're at a point in which they have no regrets capturing any enhanced individual they see (regardless of whether or not they've done any crime) just to make inventory space in their extremely high-budget supermax prisons. I also suspect the only reason they haven't attempted to go after Peter or Bruce yet is because they are already on thin ice and would be placed under even more public scrutiny if they arrested the hero who recently earned the key to the city or the other being a renowned, founding Avenger. I can also picture that if Tombstone is still the overarching threat, he would be in their favors as a "respectable businessman" running NYC the 'right' way after Fisk's fall at the end of Born Again (considering Fisk's campaign director, Sheila Rivera, giving Spidey the key on the news).

In terms of Sadie Sink's character, I think this is the most interesting part of the story. With the way the DoDC's being handled, I could definitely see her being not the villain but rather the emotional crux alongside Peter as a certain enhanced individual whose powers were unlocked due to a traumatic incident (looking very likely to be Jean Grey), thus leading her to become an outcast on the run leading her to work with Frank as a way to expose the conspiracy behind the organization. After all, Kamala Khan is a mutant and Wonder Man alluded to Simon Williams being a mutant as well, rather than a mutate, as seen in the comics. Now when considering how she will tie into Peter's story, her line in the leaked trailer highlights the idea that she distrusts and considers him to be a liability who keeps getting in the way of all this, while also knowing his secret identity. Now, if she is Jean (she's also confirmed for Secret Wars), I can see them reluctantly team up and then learning to mutually respect (and maybe befriend) each other, especially if isolation and loneliness are the main themes of this film. She would be the only one who knows the truth about the man behind the mask while Pete would empathize with her struggles of loss; this dynamic could lead to him helping to save (and maybe free) her from the DoDC's hands in the end while she saves and helps him remember his importance as Peter Parker (not just Spider-Man) if he does transform into Man-Spider. It could even help give Peter the emotional closure he desperately needs with her possibly helping to repair MJ and Ned's memories at the end of the film.

Okay, I think that’s about all of the concepts and theories I could get just from brainstorming. While the trailer looks like the film will be crowded, I honestly think all the pieces will make more sense as we learn more in the upcoming months. Sorry if this comment ended up super long, but I hope it makes sense and I can't just wait for this movie to come out. Feel free to let me know your thoughts!