In addition to any unresolved plot points that carry over from the current season (as mentioned by Kasey in another answer), I personally think the final season will see the boys working to eradicate evil from the world once and for all. All angels go back to Heaven, all demons go back to Hell, all monsters go to Purgatory, and the gates to all of them are shut and sealed forever, beyond any shadow of a doubt.
Furthermore, I think the final season will really drive home the theme of family, even more so than it has done over its entire run. I feel like the boys will be tested more than they ever have, which says a lot. Their trust in each other, their bonds, their loyalties.
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