Reply to an email is sent to reply address which can be something same as error address or an organisation specific email inbox.
If you keep the reply address to be organisation specific then it has to either be monitored manually by a team or you design a specific application that reads these messages for keywords and can then fire an API call to unsubscribe the recipient.
If the reply address is same as error address, then Campaign module inMail reads this inbox. You can write MX inbound management rules to decide what needs to be done for such response.
I did a test in ACS using same reply-to and error address, sent email and replied with "unsubscribe" in the subject but the profile is not blacklisted. Also reached out to deliverability team and they are not aware it is possible to blacklist if someone replies with 'unsubscribe' in subject/body.
Just wanted to confirm writing inbound rules is not possible to process unsubscribe requests in ACS?