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Suppression of CD8 T cells by itaconate: mechanism and therapeutic potential

Award Number: R01CA314300
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/03/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Suppression of CD8 T cells by itaconate: mechanism and therapeutic potential - Project Summary The tumor microenvironment possesses metabolic mechanisms that suppress anti-tumor immunity. Itaconate is a metabolite produced from the Krebs cycle intermediate cis-aconitate by the activity of immuneresponsive gene 1 (IRG1). We recently demonstrated itaconate can be secreted by immune suppressive myeloid cells and taken up by CD8+ T cells, resulting in significant reductions in proliferation, antigen-dependent cytotoxicity, expression of inflammatory cytokines and the key cytotoxic effectors granzyme B and perforin. Metabolite profiling and stable-isotope tracing studies indicated that itaconate reduced the levels of aspartate, serine, and glycine in CD8+ T cells. Importantly, supplementation of aspartate, serine, and glycine together reversed the inhibitory effects of itaconate on CD8+ T cell proliferation, supporting a key role for perturbing their biosynthesis in mediating the biological effects of itaconate on CD8+ T cells. Using the Irg1 knockout mouse model, we further demonstrated that loss of Irg1 resulted in decreased growth of allografted melanoma and CRC tumors, promoted anti-tumor immunity of CD8+ T cells, and enhanced the anti-tumor activity of anti-PD-1 antibody treatment. Similar pro-tumor functions of IRG1 and itaconate have been very recently confirmed by several other studies in various cancer mouse models. However, there are significant knowledge gaps on the molecular mechanisms underlying the role of itaconate in tumor immunity. Based on our recent discovery, we hypothesize that itaconate plays a critical role in suppressing CD8+ T cell mediated anti-tumor immunity in the tumor microenvironment. In Aim 1, we will characterize how CD8+ T cells take up itaconate secreted from immune suppressive myeloid cells. We will investigate whether a candidate transporter mediates the itaconate uptake in CD8+ cells. In Aim 2, we will investigate the molecular mechanism underlying the inhibitory effects of itaconate on CD8+ T cells. We will characterize a candidate itaconation target in the serine biosynthesis pathway that was revealed in our preliminary studies. We will also identify and characterize additional novel targets of itaconate in CD8+ T through a chemo-proteomic approach. In Aim 3, we will explore the therapeutic effects of IRG1-targeting siRNA nanoparticles (NP) in mouse tumor models. We will explore a unique lipid-polymer hybrid NP platform developed in the laboratory of Dr. Jinjun Shi (Co-Investigator) to deliver Irg1 siRNA to tumors. In addition to tumor immunology, identification of transporter(s) and downstream targets of itaconate in T cells will likely impact other areas of itaconate research as well, including its role in autoimmune, inflammatory, and infectious diseases. The use of a murine tumor model is essential for this study to observe the complex, systemic interactions between tumor cells and the immune system that cannot be replicated in vitro, and to evaluate the efficacy of the proposed therapeutic within a complete living organism


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 = $627,733 )
2026	2026	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	1	7/7/2026	NEW	$627,733
														Subtotal = $627,733

Grand Total All Awards = $627,733

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Suppression of CD8 T cells by itaconate: mechanism and therapeutic potential

Award Number: R01CA314300

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/03/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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