Have you ever played Minecraft? Or Terraria? Or Dwarf Fortress?
I'm willing to bet the answer is no, but those games both have a theme that I think fits really well with D&D; clearing out untamed wilderness to eek out a slice of society while slaying monsters and finding treasure. In fact, clearing out wilderness was what PCs were supposed to do in AD&D 1e when they reached Name level.
There's even a sense of reclaiming a post apocalyptic world in Terraria and Minecraft, fueled on by the lack of people, the zombies everywhere and the ancient ruins littered with treasure. Not to mention the encroaching evil in Terraria that forms an overall story arc.
I think you could actually make a really awesome D&D campaign based off of Terraria. I've seen one person make one based off of Pokemon Red/Blue which actually seemed incredibly interesting. The plot would look something like this:
PCs are sent by a kingdom across the sea to reclaim a lost continent/territory. That, or maybe there was some grand disaster and they're left in a scenario like that. Since they're basically settlers, they need to do all that entails; clear forest, build a shelter, find food and water, etc. They'd also need to fight off waves of zombies and demonic eyeballs, maybe finding NPCs who can give them help (a nurse, a merchant, a weaponsmith, etc).
Let them explore caves and find artifacts and magic items. Let them stumble across a large swath of land blighted by The Corruption. Travel through frozen tundras and perilous jungles. Maybe find the remains of a Necropolis guarded by an old man who is the host for a giant skeletal monster.
This wasn't related to your original question, but I think you'd find it of some interest. Or at least I hope you will!