"What is this lesson about?"

Translation: O czym jest ta lekcja?

[MeganKunze1]

Which grammatical case would the answer to this question be?

[Jellei]

When "o" means "about" (so mostly), it takes Locative. Ta lekcja jest o poezji. (This lesson is about poetry).

[Hereandthere715]

o co chodzi ta lekcja?

[alik1989]

You'll need w+locative. O co chodzi w tej lekcji?

[Glen624972]

Would "O czym to ta lekcja?" have been accepted?

[alik1989]

To only works with nouns on both sides.

[Glen624972]

OK, thank you

[joshmcguir11]

Explain czyms

[Jellei]

It's "czym" here. It's the Locative form of "co", meaning "what".

"czymś" is the Locative form of "coś", meaning "something".