The Metroid Prime Trilogy is about cancer.
I often wonder while playing it how much teamwork went on between Retro and Nintendo, because the central theme of the series is virtually unique to Japan: radiation. In fact, I can’t think of any other whole culture in which "radiation" could be considered an honest-to-god theme along the lines of destiny or daddy issues. Some may say that the theme is more broadly about corruption, and that radiation is merely an aspect of this. But it’s pretty hard for me to look at the conflict of the series (outside force falls from above to envelop the world in destruction and lasting radiation that warps everything it touches) as something that isn’t intrinsically about Nagasaki and Hiroshima.
The enemy of the series is twofold: Metroid Prime (later taking the form of Dark Samus) and Phaaze, a sentient planet. The latter is, in essence, a galactic tumor. It has no purpose but to grow, corrupt, and destroy its host. It metastasizes through meteors, turning other planets into lifeless husks until nothing remains but Phazon. It never speaks, it isn’t itself anthropomorphized (allowing the human-like role to be filled by its agent) and it has no greater ambitions. It is a primal, mindless, unrelenting force of destruction from the inside out.
Dark Samus, on the other hand, is a personification of the individual effects of cancer on its victims. After Samus defeats its original form, a gigantic corrupted Metroid (which, fittingly, first resembles a crab) the monster literally steals Samus’s image. Phazon may be the cancer, with Phaaze at its malignant core, but Dark Samus is what we really fear most about the disease: something is trying to take our entire body away from us.
The third and final game in the trilogy makes the theme of cancer most obvious, what with the introduction of Phaaze’s larger plot and Samus’s own deteriorating health, but Phazon’s role in all three games is cleanly tied with cancer. It starts at a source and spreads. It grows whatever is exposed to it. It feeds off life. It lies dormant, underneath the surface of visible symptoms.
There are other elements of the series and Metroid as a whole that are obviously also present, such as isolation and human-versus-nature; to me, the most powerful image in the trilogy is when Samus removes her helmet to take one last look at the ruins at Tallon IV, showing that despite her incredible feats she’s still only human. But when I remember Metroid Prime, I don’t think of Samus going it alone like in Super Metroid, or wiping out aliens left in right like in Metroid II. I think about the time when I suited up, powered through and killed cancer.