# Role of lipid metabolism in CD8+ T cell ferroptosis > **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2024 · $460,310 ## Abstract PROJECT SUMMARY Recently, we made a novel and exciting discovery that tumors or the tumor microenvironment (TME) cause T- cell dysfunction and death by inducing ferroptosis in T cells. We analyzed the sc-RNA-seq data of tumor- infiltrating T cells from melanoma patients and discovered that tumor-infiltrating CD8+ T cells had significantly increased expressions of genes associated with lipid peroxidation and ferroptosis compared to blood CD8+ T cells from healthy individuals. More importantly, our unpublished studies further revealed that among different CD8+ T cell subpopulations, effector memory (TEM) and terminally differentiated effector (TTE) CD8+ T cells are more sensitive to tumor-induced ferroptosis. We examined tumor-infiltrating CD8+ T cells from the bone marrow (BM; tumor bed) of patients with multiple myeloma. By separating the T cells into naïve, TTE or TEM cells based on their expression of CCR7 and CD45RA, we found that TEM and TTE CD8+ T cells expressed higher levels of lipid peroxidation- and ferroptosis-associated genes and were more sensitive to tumor-induced ferroptosis compared to naïve CD8+ T cells although they expressed similar levels of CD36. Similarly, in mouse melanoma and MM models, increased ferroptosis mainly occurred in tumor-infiltrating CD8+ TEM and TTE cells but not in naïve CD8+ T cells from mice with large tumor burdens compared to those with small tumor burdens. Our ex vivo studies confirmed that CD8+ TEM and TTE cells were more sensitive to tumor- or FA- induced ferroptosis than naïve T cells and their production of cytotoxic cytokines such as IFNγ and TNFα was inhibited. To elucidate the underlying mechanisms, RNA-seq was used and showed that CD8+ TEM and TTE cells expressed a significantly lower level of 2,4-dienoyl-CoA reductase 1 (DECR1), a rate-limiting enzyme for polyunsaturated fatty acid (PUFA) β-oxidation, compared to naïve CD8+ T cells. Knockdown (KD) of DECR1 in naïve CD8+ T cells resulted in an increased PUFA expression and peroxisomal dysfunction and sensitized them to tumor- or FA-induced ferroptosis than control T cells. Based on these novel findings, we hypothesize that CD8+ TEM and TTE cells, due to uptake of more FAs and reduced expression of DECR1 and PUFA oxidation, are sensitive to tumor/TME-induced ferroptosis, and inhibiting TEM and TTE cell ferroptosis may effectively enhance the therapeutic efficacy of immunotherapy in cancer patients. Aim 1 will determine the mechanism underlying tumor- or FA-induced ferroptosis in CD8+ TEM and TTE cells in TME. Aim 2 will elucidate the role and mechanisms of tumor and TME accumulation of FAs and induction of lipid peroxidation in CD8+ TEM and TTE T cells and Aim 3 will inhibit CD8+ TEM and TTE cell ferroptosis to enhance the efficacy of cancer immunotherapies. Accomplishing these aims will provide us with in-depth understanding of the mechanisms underlying how tumors and the TME induce T cell lipid peroxidation and how ferroptosis mediates T cell met... ## Key facts - **NIH application ID:** 10931709 - **Project number:** 5R01CA278787-02 - **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE - **Principal Investigator:** Qing Yi - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $460,310 - **Award type:** 5 - **Project period:** 2023-09-19 → 2028-08-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10931709 ## Citation > US National Institutes of Health, RePORTER application 10931709, Role of lipid metabolism in CD8+ T cell ferroptosis (5R01CA278787-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10931709. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*