Generally speaking, you should focus on upgrading the newest 3 star characters being rammed out into the game before anything else. Why? Because they tend to be the best and most overpowered.
Who you upgrade at 3 star will of course depend on what you draw for covers, who is offered in the DDP, and how much money you want to spend for cover packs.
As a guy who plays daily, and has done so for 600 days I’ll give you my thoughts..
For old school 3 star characters, Hulk, Steve Rogers, Magneto and Thor are probably the ones you’d like to have. Despite the changes in the game, and the character trajectory, those old school guys are really useful.
For new school characters, who are either politically correct, or fall in line with Marvel’s agenda ( movie or comic ), you are well advised to upgrade Luke Cage, Iron Fist, Cyclops, Kamala Kahn, Captain Marvel. If you get Black panther covers ubiquitously, esp. black, then he is one to focus on as well.
After that, tweener characters like Gamora, Rocket/Groot, Deadpool, Grey Suit Black Widow, Mohawk storm, psylocke, colossus can be looked at as decent if you have the resources.
A couple of characters are unique in that they are underpowered but serve a player well in specific circumstances. These are notably Hood and Loki. Mostly useful if an adversary has them in PVP. But otherwise useful in specific situations.
Characters with natural healing, i.e patch wolverine and daken, are decent, but generally for me, are not go to characters. I’ve not used Daken much at all outside of when he’s buffed, and patch Wolverine is periodically useful - especially when paired with Loki and Magneto.
Characters like Doc Doom, Mystique and Spiderman are useful in some situations, otherwise fringe.
After that, for me anyway, characters like doc oc, beast, vision, iron man model 40, sentry, she hulk, daredevil, are borderline useless unless featured ( which is the only reason to keep them ).
So yeah, in a perfect world upgrade the new 3 star characters, and the select old school ones