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I think they gave Serena the redesign (which makes her very different from her in-game counterpart and is even impossible to replicate in the game) with the intention of potentially reusing her later on, for roughly the same reason thry made Ash different from Red. Now I say only "potentially", in that they got wind of her popularity and didn't want to leave her locked to a gen/game just in case they wanted to do something with her in the future.
She will never return as a permanent cast member unless the anime is dying, but good writing can make cameos not be so awkward. Say, she shows up in Alola, blush here and there, has adventure, episode ends with her and Ash walking in the beach alone: no "THEY'RE A THING" thrown on your face, but repercussions of kissu are still implied, then she's gone again.
