Cysteine supplementation reverses immune dysfunction in cancer patients with severe COVID-19
- 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center; New York, NY, USA
Abstract
Severe COVID-19 infection in patients with cancer is characterized by a unique pattern of immunologic dysfunction including muted adaptive immune responses. The molecular drivers of immune dysfunction in cancer patients with severe COVID-19 remain unclear, and therapeutic strategies to overcome immune dysfunction in this setting have not been identified.
We performed integrated proteomic and metabolomic profiling of matched cohorts of cancer and non-cancer patients with or without COVID-19 and identified dysfunctional cysteine metabolism as uniquely associated with severe COVID-19 in cancer patients. Treatment of patients with cancer and steroid-refractory COVID-19 with N-acetylcysteine in a prospective clinical trial (NCT04374461) improved clinical outcomes compared with disease severity-matched hospitalized patients during the period immediately preceding clinical trial initiation. N-AC treatment 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 we confirmed was sufficient to limit T cell expansion and effector differentiation in a dose- and avidity-dependent fashion. Moreover, N-AC reduced the activity of inhibitory, redox sensitive transcription factors such as KLF6, enabling clonal expansion and effector T cell differentiation. We confirmed these observations in two murine models of severe respiratory viral infection, in which N-AC treatment significantly enhanced lung-infiltrating CD8+ T cell abundance. These 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.
One Sentence SummaryMerlinsky et al show that cysteine supplementation can therapeutically reverse immune dysregulation in cancer patients with severe COVID-19 infection.
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BibTeX
@misc{merlinsky2026cysteine,
title = {{Cysteine supplementation reverses immune dysfunction in cancer patients with severe COVID-19}},
author = {T. Merlinsky and J. Rahman and W. T. Johnson and L. McGary and S. Grassmann and J. Zhang and A. Abdulraouf and H. L. Kalvin and K. Panageas and J. Nicodemus and E. Cathcart and Y.-H. Lin and K. K. Hosszu and M. Berisa and O. Lyudovyk and G. Salles and J. J. Boelens and N. E. Babady and J. Cao and J. D. Wolchok and J. C. Sun and J. Heath and B. Greenbaum and S. Vardhana},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.26363550},
url = {https://www.medrxiv.org/content/10.64898/2026.09.21.26363550v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Cysteine supplementation reverses immune dysfunction in cancer patients with severe COVID-19
AU - T. Merlinsky
AU - J. Rahman
AU - W. T. Johnson
AU - L. McGary
AU - S. Grassmann
AU - J. Zhang
AU - A. Abdulraouf
AU - H. L. Kalvin
AU - K. Panageas
AU - J. Nicodemus
AU - E. Cathcart
AU - Y.-H. Lin
AU - K. K. Hosszu
AU - M. Berisa
AU - O. Lyudovyk
AU - G. Salles
AU - J. J. Boelens
AU - N. E. Babady
AU - J. Cao
AU - J. D. Wolchok
AU - J. C. Sun
AU - J. Heath
AU - B. Greenbaum
AU - S. Vardhana
PY - 2026
DA - 2026/09/21
PB - medRxiv
DO - 10.64898/2026.09.21.26363550
UR - https://www.medrxiv.org/content/10.64898/2026.09.21.26363550v1
AB - Severe COVID-19 infection in patients with cancer is characterized by a unique pattern of immunologic dysfunction including muted adaptive immune responses. The molecular drivers of immune dysfunction in cancer patients with severe COVID-19 remain unclear, and therapeutic strategies to overcome immune dysfunction in this setting have not been identified. We performed integrated proteomic and metabolomic profiling of matched cohorts of cancer and non-cancer patients with or without COVID-19 and identified dysfunctional cysteine metabolism as uniquely associated with severe COVID-19 in cancer patients. Treatment of patients with cancer and steroid-refractory COVID-19 with N-acetylcysteine in a prospective clinical trial (NCT04374461) improved clinical outcomes compared with disease severity-matched hospitalized patients during the period immediately preceding clinical trial initiation. N-AC treatment 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 we confirmed was sufficient to limit T cell expansion and effector differentiation in a dose- and avidity-dependent fashion. Moreover, N-AC reduced the activity of inhibitory, redox sensitive transcription factors such as KLF6, enabling clonal expansion and effector T cell differentiation. We confirmed these observations in two murine models of severe respiratory viral infection, in which N-AC treatment significantly enhanced lung-infiltrating CD8+ T cell abundance. These 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. One Sentence SummaryMerlinsky et al show that cysteine supplementation can therapeutically reverse immune dysregulation in cancer patients with severe COVID-19 infection.
ER -