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Again, just like it depends on your team of heroes, it really comes down to your team of villains. Certain villains synergize with each other better, like Citizens Hammer & Anvil alongside Challenge Mode Fright Train.
Good to know. Any other combos to look out for?
If you are avoiding challenge for now, I would recommend against Ambuscade, Baron Blade, and (If you rely on setup heavy heroes) Ermine.
Most of the rest I have found to be sometimes easy, and sometimes hard. I personally find Miss Information and the Operative to be the easiest team villains.
Sarge Steel is painful, but only has 20 health and next to no actual protection for himself, so he's mostly an early threat.
Biomancer is just a pain to kill, most of the time he doesn't do all that much, but he and Proletariat tend to outlast everyone else easily. Proletariat at least runs out of clones to hide behind, Biomancer just has passive -2 to first damage each turn and heals 2 on his turn.
Greazer falls into same category as Steel, but for different reasons. He's decently tough but highly focused on killing one hero and leaves once he has, so if things go well you kill him, if things go south he's gone, if things don't he can be beaten normally. Also really depends on who his nemesis for the game is. I hear he really is going to hate Akash'Thriya once Oblivaeon hits.