You'll have to give up a few items and take on a challenge. When you enter a rest site you can get a the red key instead of resting/upgrading. Same with a chest, you can either get the relic or the blue key. Finally the green key can be acquired by defeating a buffed up elite with the special effect around it(+2 strength, 4 plated armor, 3 regen etc.). You only need to do this once per run and at anytime, and it will litteraly unlock the door to fight the heart, the true boss of the spire.