Clearly, it is difficult to fight spam on the supply side. The less obvious way and most effective is to look on the demand side. Take away the demand and the supply of spam stops.
Now, there is only a really tiny portion of the recipients of spam that actually appreciates it and responds to the
offers. How to identify them?
Each Internet Service Provider writes a message to all their users in the best spam tradition.
All the users who respond to that message are then identified as the cause of spam. Smart users find an opt-out option (on the anti-spam pages of the ISP) soon enough and are not bothered again. The opt-out is also mentioned in the auto-reply when mailing to abuse@yourisp.
The spam respondents are then educated and asked never to respond to spam again.
An ISP can include a paragraph in the user agreement that the user shall not endanger the systems of the ISP. Many ISPs have such a statement already. The ISP can make explicit that responding to spam is part of this agreement.
That would do decrease the number of spam respondents. The profitability of spam disappears and spam goes down with it.