I considered putting The Binding of Isaac on this list, but ultimately decided against it. While that game is extremely difficult for new players, once one has "learned" the game it becomes much easier and based more around RNG. Enter the Gungeon, on the other hand, is almost entirely skill-based, to the point where I've never beaten the final boss.
Like Isaac, the game is a rouge-like, meaning the layout of the floors are randomly generated each time you play and death is permanent. Each floor is exponentially more difficult than the last, as the game throws more and more complex enemies at you. The bosses in particular are extremely challenging bullet hells, and as if that weren't enough, the only reliable way of upgrading your health is to beat a boss without getting hit once. Seeing the true final boss and ending of this game is an achievement you should feel truly proud of.