It doesn't seem to be profitable, in part because the internet now consists of mega-sites and if your network doesn't serve ads on the mega-sites, no one is interested in your network.

Project Wonderful was a fantastic webcomic-focused ad network. From my perspective as a reader, being shown ads for other webcomics while I'm reading a webcomic was... a positive, really. A lot of webcomic artists ran Project Wonderful ads and nothing else. They shut down in part because of the rise of facebook.