The game cleverly deals with the issue of certain characters being vastly more powerful than others by making the objective of a match "who can control a location better?" instead of "who can destroy the other side first?". Raw power isn't the end-all-be-all (though it certainly plays a big part) when it comes to holding a location, after all, and there are a few examples:
Red Skull has a power level around that of cosmic-level entities at 14, despite normally being much weaker than them. In his case, he has an entire organization in HYDRA to infiltrate and capture the location.
Alioth, a trans-temporal Eldritch Abomination that destroys everything in its wake, only has 3 power—mindlessly destroying everything it touches does help to remove the opposition (as shown by its ability), but isn't as helpful at capturing a location in good condition.
Galactus is a Planet Eater, and if he's played on a winning location on his own it reduces the playing field to one location, which is useful to control a single location, but only brings 5 power and isn't helpful in capturing a location in good condition.
She-Hulk's power is that she is 1 Energy cheaper for unspent energy on the previous turn. In essence, a player can pre-pay to play her on a subsequent turn. Like keeping a lawyer on retainer.
Goose and The Big House prevent cards costing 4, 5, and 6 from being played. There is no connection to each other in the comics, but they do have something in common: Goose has a Black-Hole Belly and can take out enemies larger than him, or contain their power; the Big House is a shrunken prison that is meant to imprison multiple large and powerful villains. The most powerful cards are 4, 5, and 6 cost, whether that power comes from raw strength or incredibly potent abilities.
M.O.D.O.K.'s one ability is to discard your hand when revealed, in a game where discarding cards is akin to killing them. Indeed, he vaporizes your entire hand with a huge laser. This makes his acronym name Exactly What It Says on the Tin: Mental Organism Designed Only for Killing! This might also explain why he's the only non-vampire, non-sword, and non-card user who has a discard ability—if we went by his acronym, he would likely have had the ability to destroy your own cards, if not for Venom, Carnage, Deathlok and Destroyer already having that role before M.O.D.O.K.'s release.
Agatha Harkness's ability has her be drawn first and play the game itself as long as she's in the player's hand and will play herself at the earliest opportunity. Being a 6 Cost card would mean a game with Agatha Harkness in a deck would potentially end with a player finding out that their opponent has essentially beenAgatha all along.
The TVA location causes the game to end on turn 4. The game's Excuse Plot involves dimensional rifts linking locations across space and time, and the Time Variance Authority's purpose is to put a stop to such temporal disturbances.
Gambit's effect relies on discarding a card from your hand and destroying a random enemy card in play; said action is Leaning on the Fourth Wall. Now who was one of the people Gambit battled before? Deadpool.
Jeff being able to be played anywhere comes from his Cuteness Proximity such as the one time he was taken care of by Elsa Bloodstone, with the latter vowing to kill anyone who wanted to hurt Jeff. In a sense, Jeff's charm allows him to be played or moved anywhere.
Grandmaster has 0 power because he's The Chessmaster who would rather pull the strings and manipulate others like pawns, which is reflected in his ability to move another on-reveal card in his location to the center location, alongside his animation involving a chessboard-like pattern and make them use their on-reveal ability again.
