Cysteine supplementation reverses immune dysfunction in cancer patients with severe COVID-19

Severe COVID-19 in cancer patients involves a distinct immunologic dysfunction profile, including muted adaptive responses, but the molecular drivers and therapeutic options were unclear. To investigate, researchers performed integrated proteomic and metabolomic profiling of matched cancer and non-cancer patients with or without COVID-19, identifying dysfunctional cysteine metabolism as uniquely associated with severe COVID-19 in cancer patients.

In a prospective clinical trial (NCT04374461), cancer patients with steroid-refractory COVID-19 received N-acetylcysteine (N-AC); compared with disease severity-matched hospitalized patients from the period immediately before trial initiation, N-AC treatment improved clinical outcomes. N-AC also reduced circulating markers of innate inflammation, decreased severe disease-associated MHC-II low monocytes, and increased circulating CD8+ T cell abundance, activation, and effector differentiation.

Mechanistically, N-AC reduced prostaglandin E2-driven interactions between suppressive monocytes and T cells, which were sufficient to limit T cell expansion and effector differentiation in a dose- and avidity-dependent manner. N-AC further reduced activity of inhibitory, redox-sensitive transcription factors such as KLF6, enabling clonal expansion and effector T cell differentiation.

The observations were confirmed in two murine models of severe respiratory viral infection, where N-AC significantly enhanced lung-infiltrating CD8+ T cell abundance. The findings establish cysteine supplementation as a viable therapeutic strategy to reverse redox-driven immune dysregulation in severe respiratory viral infection, particularly in the high-risk cancer population.