How about a game where your protagonist finds an entrance to a cave near his/her home and goes exploring. Until, an earthquake causes a cave in which you narrowly avoid but end up landing into a mysterious pool of glowing water filled with illuminant micro-organisms. This causes some noticable changes in your character, to better adapt to your current habitat and your story is either finding your way out, or finding a cure THEN finding your way out, or finding a underground society of similar creatures which you can communicate with and stay with them, OR you could travel even further until you vanish from the games story or you could find even stranger or harder endings.
The gameplay would deal with how to interact with the vast network of cave systems you would encounter. Tools are still necessary, which you could create from combining items found in the environment. Not all of the environment is friendly though, with plants, animals and others possibly becoming your foe, depending on how you act. Would you befriend a race of wolf type creatures to gain some allies and needed food, or help to protect a underground forest of fungi in order to safely harvest it? Will you unlock a ancient door in order to free the black shades within?
As you are still an organism, energy is needed to continue breathing so you must always have a source of food and water to eat, though thanks to your mysterious changes you wont need to feed as frequently as others may. But food and water isnt everything you need, as you will discover.
... Wow I really went on a idea breakthrough there didnt I? I really cant believe I came up with an idea like this. I sure would play it, would anyone else though? be honest, or no toes for you. Also, I wouldnt be surprised if a Deep Crow (Penny Arcade) managed to find its way into there.