Formate Supplementation Enhances Antitumor CD8+ T-cell Fitness and Efficacy of PD-1 Blockade
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Abstract
The tumor microenvironment (TME) restricts antitumor CD8+ T-cell function and immunotherapy responses. Cancer cells compromise the metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate that one-carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T-cell fitness and antitumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T-cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti–PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for enhanced tumor control. Our data demonstrate that formate provides metabolic support to CD8+ T cells reinvigorated by anti–PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T-cell function. Significance: This study identifies that deficiencies in 1C metabolism limit the efficacy of PD-1 blockade in B16-OVA tumors. Supplementing 1C metabolism with formate during anti–PD-1 therapy enhances CD8+ T-cell fitness in the TME and CD8+ T-cell–mediated tumor clearance. These findings demonstrate that formate supplementation can enhance exhausted CD8+ T-cell function. See related commentary by Lin et al., p. 2507. This article is featured in Selected Articles from This Issue, p. 2489
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Pretreating human colorectal adenocarcinoma HT-29 cells with formate in vitro sped up tumor growth in immunocompromised mice.
“In vitro formate-pretreatment of human colorectal adenocarcinoma HT-29 cells accelerated tumor growth in immunocompromised mice91.”
From Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy (2025) · cites this paper as [91]
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Re-“Formate” T-cell Antitumor Responses
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- Authors
- Rowe, J. H., Elia, I., Shahid, O., Gaudiano, E. F., Sifnugel, N. E., Johnson, S., Reynolds, A. G., Fung, M. E., Joshi, S., LaFleur, M. W., Park, J. S., Pauken, K. E., Rabinowitz, J. D., Freeman, G. J., Haigis, M. C., & Sharpe, A. H.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Princeton University (US)
- Corresponding author
- Haigis, Marcia C.
- Sharpe, Arlene H.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2023-09-20
- Volume
- 13
- Issue
- 12
- Pages
- 2566-2583
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC10843486
- OpenAlex
- W4386878350
- Cited by
- 59
- References
- 51
- Citations by year
- 2026: 23 · 2025: 20 · 2024: 15 · 2023: 1
- FWCI
- 7.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Lirias (submittedVersion)
- Funders
- Roche (N/A)
- Ludwig Center (N/A)
- Office of Extramural Research, National Institutes of Health (P50 CA101942, U54 CA224088, R01 CA276866, P01 AI56299)
- Glenn Foundation for Medical Research (N/A)
- Cancer Research Institute (CRI4006, CRI3352)
- European Molecular Biology Organization (ALTF-1078-2017)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- one-carbon metabolism, CD8+ T cells, anti-PD-1 therapy, tumor microenvironment, T cell metabolism, T cell exhaustion, antitumor immunity, B16-OVA tumor, combination immunotherapy, tumor-infiltrating T cells
- MeSH terms
- Formates, Humans, Neoplasms, CD8-Positive T-Lymphocytes, Dietary Supplements, Tumor Microenvironment, Programmed Cell Death 1 Receptor
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