The lead role of John Doe is played by Black actor Anthony Mackie, paired with Latina actress Stephanie Beatriz as the axe-wielding co-lead Quiet, establishing a diverse central duo in a post-apocalyptic setting. The narrative incorporates class inequality as a recurring subplot, contrasting walled 'Insider' cities with exploited 'Outsiders,' framing society in terms of haves versus have-nots with anti-capitalist undertones highlighted by cast comments on real-world class war.

Quiet receives bisexual hints and queer-coded moments, including a convoy scene with explicit gay music cues, while Sweet Tooth carries kink and potentially queer-coded vibes. These elements influence character backstories and subplots without dominating the core road-trip delivery premise or car combat action. No major source-material race or gender swaps of iconic game characters occur, and messaging remains secondary rather than lecture-heavy or premise-collapsing, placing it in the noticeable but non-central range.