Quick Answer: The best comic books become lasting pop culture references when they introduce ideas, images, or phrases that fill gaps in the existing cultural vocabulary. Watchmen gave critics a framework for the morally compromised superhero. Maus showed what sequential art could do with trauma. Spider-Man gave everyone 'great power, great responsibility.' These works stopped being comics for fans and became shorthand for anyone trying to talk about heroism, history, or responsibility.
Most people who say 'with great power comes great responsibility' have no idea the line was refined across decades of Amazing Spider-Man issues before Sam Raimi's 2002 film made it permanent. That's what full cultural crossover looks like, the reference outlives its source, detaches from the medium, and becomes part of the shared language everyone speaks without attribution.
Comic books are a type of sequential art medium that uses a combination of illustration and text to tell stories. The best comic books differ from average ones not in production quality but in the density of their ideas, the number of concepts they introduce that have no precise equivalent in any other form.
That gap-filling quality is what determines which comics become pop culture references and which remain beloved genre fiction. It's not about sales or critical reception at time of release. Watchmen sold moderately when DC published it in 1986 and 1987. Its cultural mass accumulated over decades as filmmakers, critics, and writers absorbed its arguments and built on top of them.