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Targeting the E3 Ligase RNF166 to Prevent T-cell Exhaustion in Solid Tumors

Award Number: R01CA315781
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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Targeting the E3 Ligase RNF166 to Prevent T-cell Exhaustion in Solid Tumors - Project Summary/Abstract T-cell exhaustion (TEX) is a major barrier to the success of adoptive T-cell therapies (ACT) in solid tumors. Driven by chronic antigen stimulation and tumor-associated environmental such as nutrient depletion. TEX is characterized by impaired effector function, loss of persistence, and elevated inhibitory receptors. We identified the E3 ligase RNF166 as a novel regulator of T-cell function: RNF166 overexpression (OE) enhances cytotoxic persistence, reduces inhibitory receptor expression, and improves tumor control in vivo. Furthermore, RNF166 expression in tumor-infiltrating lymphocytes correlates with responsiveness to immune checkpoint blockade in melanoma patients, highlighting clinical relevance. We propose to explore the mechanistic relationship between RNF166 and TEX, TIL cell fate, and CAR-T cell function in solid tumors. This application will define the role of RNF166 in regulating TEX and evaluate its therapeutic potential in ACT. Aim 1 will identify the molecular targets of RNF166 using cutting edge proteomic approaches including measurements of protein turnover, ubiquitination and protein-protein interactions. Aim 2 will test the impact of RNF166 OE or knockout on T-cell differentiation and persistence in murine tumor and viral infection models. Aim 3 will test the translation of these findings into human CAR-T cells, assessing whether RNF166 OE enhances therapeutic efficacy in liquid and solid tumor models. By uncovering how RNF166 regulates proteome integrity and exhaustion, this work will provide the first mechanistic insight into an E3 ligase as a therapeutic target in T-cells. Successful completion of these studies will establish RNF166 as a strategy to enhance T-cell persistence, overcome exhaustion, and improve the efficacy of ACT in solid tumors.


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 = $591,533 )
2026	2026	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Cancer Treatment Research	000	1	7/6/2026	NEW	$591,533
														Subtotal = $591,533

Grand Total All Awards = $591,533

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Targeting the E3 Ligase RNF166 to Prevent T-cell Exhaustion in Solid Tumors

Award Number: R01CA315781

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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