Cancer cells acquire cysteine directly from a reduced tumor microenvironment

Abstract

The metabolic environment of a tumor is shaped by the nutrients available in its interstitial fluid, yet the redox composition of that fluid is poorly defined. Measuring sulfur metabolites in the interstitial fluid of tumors, matched healthy organs, and serum across three mouse models of cancer, we find that the tumor microenvironment (TME) is a chemically reduced compartment in which free cysteine predominates over its oxidized form, cystine. This is especially pronounced in the lung TME, where cystine is nearly absent. We further show that lung cancer cells take up cysteine and cystine with comparable efficiency and proliferate on cysteine alone, and that the abundant glutathione in the TME helps keep cysteine reduced through disulfide exchange. In a medium formulated to match the sulfur composition of the lung tumor interstitial fluid, cells become independent of cystine import through xCT. Cells cultured in this medium were resistant to glutaminase inhibitors, oxidants and ferroptosis inducers, and better maintained NADPH levels under oxidative challenge. These findings suggest that standard culture conditions overestimate the dependence of cancer cells on cystine uptake and their vulnerability to oxidative stress-targeting therapies.

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BibTeX RIS

BibTeX

@misc{choudhury2026cancer,
  title = {{Cancer cells acquire cysteine directly from a reduced tumor microenvironment}},
  author = {Feroza K. Choudhury and Basma A. Yasseen and Paloma González-Sánchez and Meredith Long and Samantha Caldwell and Pritin N. Soni and Suehelay Acevedo-Acevedo and Yun Huang and Elsa R. Flores and Chang Jiang and Nathan P. Ward and Gina M. DeNicola},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.25.761647},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.25.761647v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Cancer cells acquire cysteine directly from a reduced tumor microenvironment
AU  - Feroza K. Choudhury
AU  - Basma A. Yasseen
AU  - Paloma González-Sánchez
AU  - Meredith Long
AU  - Samantha Caldwell
AU  - Pritin N. Soni
AU  - Suehelay Acevedo-Acevedo
AU  - Yun Huang
AU  - Elsa R. Flores
AU  - Chang Jiang
AU  - Nathan P. Ward
AU  - Gina M. DeNicola
PY  - 2026
DA  - 2026/10/25
PB  - bioRxiv
DO  - 10.64898/2026.10.25.761647
UR  - https://www.biorxiv.org/content/10.64898/2026.10.25.761647v1
AB  - The metabolic environment of a tumor is shaped by the nutrients available in its interstitial fluid, yet the redox composition of that fluid is poorly defined. Measuring sulfur metabolites in the interstitial fluid of tumors, matched healthy organs, and serum across three mouse models of cancer, we find that the tumor microenvironment (TME) is a chemically reduced compartment in which free cysteine predominates over its oxidized form, cystine. This is especially pronounced in the lung TME, where cystine is nearly absent. We further show that lung cancer cells take up cysteine and cystine with comparable efficiency and proliferate on cysteine alone, and that the abundant glutathione in the TME helps keep cysteine reduced through disulfide exchange. In a medium formulated to match the sulfur composition of the lung tumor interstitial fluid, cells become independent of cystine import through xCT. Cells cultured in this medium were resistant to glutaminase inhibitors, oxidants and ferroptosis inducers, and better maintained NADPH levels under oxidative challenge. These findings suggest that standard culture conditions overestimate the dependence of cancer cells on cystine uptake and their vulnerability to oxidative stress-targeting therapies.
SN  - 2692-8205
ER  -

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