When the final boss battle starts, you'll be confronted by the illusion of Isaac's dead girlfriend, Nicole. It is essential to keep her at a distance, since if she grabs you, that's a game over.
Shoot the illusion of Nicole to reveal a large glowing yellow heart, the true weak point. Each time you shoot the heart, Nicole will reapear, and you repeat the process. She'll be accompanied by some necromorphs who will generously drop ammo and health.
Once the heart takes enough damage, the fight is over.