Wednesday, January 21, 2026 1/21/2026

Defining mechanisms to promote antitumor immunity by modulating one-carbon metabolism

Award Number: R01CA276866
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

Group Awards By:

View Award Description

Defining mechanisms to promote antitumor immunity by modulating one-carbon metabolism - Immune checkpoint blockade (ICB) targeting PD-1 and its ligand PD-L1 has revolutionized cancer therapy, but only a subset of patients respond, highlighting the critical need to investigate mechanisms of anti-tumor immunity to identify novel targets to enhance the effects of ICB. The goal of this project is to determine mechanisms by which one-carbon (1C) metabolism can be modulated to improve the efficacy of PD-1 blockade. We recently identified 1C metabolism, which allows cells to utilize serine or glycine to generate 1C units for nucleotides, NADPH, and glutathione biosynthesis, as the most induced metabolic pathway during T cell activation. We also discovered that there are deficits in serine and glucose levels in the tumor microenvironment (TME). Strikingly, restoring 1C metabolism by formate supplementation increases the effectiveness of anti-PD-1 treatment and tumor clearance in mouse tumor models. We hypothesize that 1C metabolism is limiting for anti-tumor T cell function and that increasing this pathway by formate supplementation can synergize with ICB to promote anti-tumor immunity. We will test this hypothesis in two aims: Aim 1: Determine cellular and molecular mechanisms by which formate supplementation improves the efficacy of PD-1 mediated tumor clearance. We will define transcriptional and epigenetic mechanisms by which 1C metabolism and formate supplementation improve CD8+ T cell function and synergize with PD-1 blockade. We will use innovative conditional knockout models and in vivo genetic perturbation studies to delete rate- limiting enzymes of 1C metabolism in CD8+ T cells, and analyze their impact on response to PD- 1 blockade. Aim 2: Determine metabolic mechanisms by which formate supplementation improves the efficacy of PD-1 mediated tumor clearance. We will use cellular and in vivo mass spectrometry-based metabolite tracing studies, and spatial metabolomics to elucidate how formate supplementation and modulation of 1C metabolism impact metabolic profiles of anti- tumor CD8+ T cells when combined with anti-PD-1. These studies will provide us with the first spatial and single cell resolution atlas of metabolic and functional immune responses in a tumor in response to ICB. We will determine how formate supplementation improves CD8+ T cell responses from the level of individual CD8+ T cells to CD8+ T cells in the metabolically heterogenous TME. Completion of these studies will be transformative by changing the paradigm of 1C metabolism in cancer treatment and demonstrating that supplementing 1C units can enhance anti-tumor immunity. Our results will inform strategies and identify novel therapeutic targets for improving cancer immunotherapy outcomes.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $506,485 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	4	12/18/2025	NON-COMPETING CONTINUATION	$506,485
														Subtotal = $506,485

Issue Date FY: 2025 ( Subtotal = $562,761 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	3	7/10/2025	NON-COMPETING CONTINUATION	$56,275
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	3	1/13/2025	NON-COMPETING CONTINUATION	$506,486
														Subtotal = $562,761

Issue Date FY: 2024 ( Subtotal = $534,622 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	2	11/22/2023	NON-COMPETING CONTINUATION	$506,486
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	2	4/17/2024	NON-COMPETING CONTINUATION	$28,136
														Subtotal = $534,622

Issue Date FY: 2023 ( Subtotal = $580,136 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	1	12/20/2022	NEW	$580,136
														Subtotal = $580,136

Grand Total All Awards = $2,184,004

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Defining mechanisms to promote antitumor immunity by modulating one-carbon metabolism

Award Number: R01CA276866

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer