In the later seasons, the Kankers seemed to stop bothering the Eds as much. I think Fistful of Ed is a big turning point for them, after Eddy tells them to leave them alone. In the episodes that would take place after, they are really just doing their own thing and leaving the Eds alone, but still explicitly having strong feelings for them. In the Big Picture Show, their only goal was to protect and defend the Eds. I think after BPS, the still lingering tension and stuff between them needs to be broken. There's still a sense of aggression and fear that needs to be dealt with, and there's already a seed planted for that, in May.
Of the three sisters, May is most likely the one to realize that the Eds "hate" them, and that the lifestyle and methods their mother uses on men simply does not work and is not good for a healthy relationship. The episode Nagged to Ed seems to show the Kankers mimicking their mom's ways while believing that that is how love is supposed to be.
From there, May may get in conflict with her sisters over that, as well as try to get Ed to actually like her and stop fearing her. If May succeeds and actually wins Ed's heart, at least to some degree, then Edd and Eddy, ESPECIALLY Eddy, will be shocked at their friend actually being close with and liking a Kanker.
Double D, being Double D, as well as remembering Hanky Panky Hullabaloo along with the Kankers coming to their rescue in BPS, may come to the conclusion that the Kankers aren't that bad, and may start to try and get close to them (read: Marie) with Ed. On the flipside, Marie may decide that May is right about their Mom's lifestyle being unhealthy and unsuccessful, and would instead follow May's example in an attempt to try and win Edd's heart.
That would leave Eddy, who would still be convinced that the Kankers are bad news, and Lee, who's the most likely to want to stick with how her mom raised her.
