What does John 15:22 mean?

The context of this statement by Jesus is important; ripped out of this discourse, these words can be grossly misinterpreted. Jesus is explaining that those who "abide in" His Word and teachings (John 15:3–5) can expect hatred and persecution from the world (John 15:18–20).

This backlash is because the unbelieving world, which does not know God, hates to be told about their sin (John 15:21). A common tactic inspired by our sin nature is seeking others to sin alongside of us—and when Christians will not do that, the response is anger (1 Peter 4:4). Likewise, our fallen human nature prefers not to be informed about our sin. We fool ourselves into thinking that if we "don't know," then it's not our fault. However, God has given us all more than enough evidence to know that good and evil exist (Romans 1:18–20), and that we ought to be seeking Him (Matthew 6:7–8).

That puts this comment into the same context as Jesus' criticism of the Pharisees in John 9:39–41. The excuse "I did not know" cannot apply to those who hear the truth and choose to attack it. Those who persecute Christians because they act like Christ are not acting in ignorance; they are following the lead of their own sinful hearts. Jesus is not saying "anyone who has never explicitly heard the gospel is innocent of sin." Rather, He is saying that those who hear His Word—including through His followers (Matthew 28:19)—have no excuse for persecuting and hating Christians.