The betrayal trope often starts with Ash's friends and even his Pokémon turning on him after some big tournament loss or false accusation. He gets framed for cheating or hurting a Pokémon, and the whole Kanto League or Professor Oak believe it without question. It's a bit melodramatic, but the appeal is in the drastic reset—Ash, alone and heartbroken, leaves to become stronger or darker, sometimes finding new mentors like a legendary Pokémon or a villainous team who actually respect him.
The best versions I've seen ditch the public humiliation parade and make the betrayal a slow, quiet thing. Maybe Brock and Misty just stop returning his calls after he loses the Indigo League again, and he realizes they were only hanging around for the adventure, not for him. The twist that gets me is when Pikachu is the one to leave, not out of malice but because it thinks it's holding Ash back. That's a gut-punch that doesn't rely on cartoonish evil from everyone.
Honestly, a lot of these stories are power fantasies, so the real plot twist is often who steps up to be his new family. I read one where Lance from the Elite Four tracks him down and offers to train him properly, seeing the raw talent everyone else ignored. That shift from being abandoned to being truly seen by a higher authority hits a specific emotional note.