'Natural' tuning is based on a mathematical principle, that the perfect 5th is a frequency multiple of exactly 3/2.
(Discovered by Pythagoras)
As you go round the 'cycle of 5th's, taking the 5th of the 5th, (C - G - D - A - E etc) and so on, you get all the other notes, but as no power of 2 is ever equal to a power of 3, you never get back to where you started. As you wander further from the original note, (into other keys) it gradually sounds more out of tune.

Equal tempered tuning is a compromise which spreads the discrepancies
equally and makes ALL keys slightly out of tune.