Most culturally isolated U.S. city?

Hey all!

Can’t think of another way to describe this. But basically, what are some American cities that have remained very unique over the years?

Have travelled to most states and large cities, and have found that while there certainly are very unique cities, many of them have the same flavor of trendy local coffee shops, sometimes regional foods, colorful murals, etc. I like all of these things but the differences between certain large cities can sometimes be minimal in terms of their non-geographic offerings.

Detroit seems fairly unique in its history, architecture, and cultural institutions. A relatively smaller major city at around 600,000 people (though its metro population is large), but with the bones and museums of a city that was once the 4th largest in the country in the 1950s.