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Targeting TOX-Imposed Epigenetic and Transcriptional Circuits to Restore T Cell Function in Cancer

Award Number: K08CA312446
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/03/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Targeting TOX-Imposed Epigenetic and Transcriptional Circuits to Restore T Cell Function in Cancer - PROJECT SUMMARY/ABSTRACT T cell exhaustion remains a major barrier to effective cancer immunotherapy, particularly in solid tumors. Exhausted T cells acquire fixed transcriptional and epigenetic states that impair their ability to proliferate, persist, and eliminate tumor cells. Transcription factors, including TOX, are central enforcers of the transcriptional and epigenetic programs that define exhausted T cells, reshaping immune cell fitness under chronic antigen exposure. However, the molecular basis of TOX-driven exhaustion remains poorly defined, and there are no scalable tools to reprogram this cell state therapeutically. The goal of this proposal is to overcome T cell exhaustion by combining mechanistic dissection of TOX-dependent regulatory networks with the design of programmable synthetic transcription factors (synTFs). The central hypothesis is that (1) TOX domains function through interactions with chromatin modulators that enforce exhaustion, and (2) synthetic transcription factors can be designed to rewire this circuitry and restore durable effector function in T cells. Aim 1 will dissect the regulatory architecture of TOX-driven exhaustion using chromatin profiling and CRISPR-based perturbation to define TOX-bound cofactors in syngeneic models of chronic antigen exposure. Targeted domain mutagenesis of TOX will identify regions critical for protein-protein interactions, and selective disruption of these interfaces will be evaluated for their impact on T cell persistence and function in vivo. Murine tumor and infection models are essential for these studies, as they enable evaluation of exhausted T cell function within an intact immune system and microenvironment that cannot be replicated in vitro. Aim 2 will establish a synthetic biology framework to reprogram exhausted T cells using modular synTFs composed of DNA-binding domains fused to epigenetic effectors. We will validate lead synTFs in primary T cells and tumor models, and perform a pooled screen of 750 constructs to discover new synthetic regulators that enhance T cell resilience under chronic stimulation. These studies will provide foundational mechanistic insights into TOX function and a new synthetic biology toolkit for rewiring T cell fate, and may inform next-generation adoptive T cell therapies for solid tumors resistant to checkpoint blockade or CAR-T treatment. To accomplish these goals, I have assembled a multidisciplinary mentorship team including Dr. Alex Marson (primary mentor), Dr. Matthew Krummel (co-mentor), and advisory members Drs. John Wherry, Brian Shy, Kole Roybal, and Arun Wiita. This training plan will prepare me to lead an independent research program that unites mechanistic immunology with synthetic biology, leveraging my clinical expertise to translate programmable transcriptional tools into T cell therapeutics.


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 = $237,546 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Research Manpower	000	1	7/3/2026	NEW	$237,546
														Subtotal = $237,546

Grand Total All Awards = $237,546

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Targeting TOX-Imposed Epigenetic and Transcriptional Circuits to Restore T Cell Function in Cancer

Award Number: K08CA312446

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/03/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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