The most straightforward way to answer the question is that off-target is kind of field lingo for “some other gene got targeted” and results in unexpected cell

The most straightforward way to answer the question is that off-target is kind of field lingo for “some other gene got targeted” and results in unexpected cell death. Imagine in bacteria, if I guide the CRISPR components to a gene that metabolizes an exotic sugar and the cell just inexplicably dies—whereas targeting that very gene in a different spot does what you expected. In eukaryotes, off-target effects likely occur more often (more genes) but we just don’t see them, because the off-target effect wasn’t immediately fatal. Instead, maybe a tumor suppressor gene got rearranged? It might take decades to see the physiological effect.