# Restoring the Immunogenicity of Head and Neck Cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $555,467

## Abstract

PROJECT SUMMARY
 Immune checkpoint receptor blockade (ICB) has been approved recently for the treatment of
metastatic, unresectable, or recurrent head and neck squamous cell carcinoma (HNC) in the first-line setting.
Multiple priming strategies have entered into trials, aiming to turn cold HNCs, which account for about 85% of
the cases, into T-cell inflamed hot tumors and expand the pool of patients who can benefit from
immunotherapy. Mechanistically, many priming strategies activate innate immune sensors to launch the
production of type-I interferons (IFN-I) by cancer cells and myeloid cells. The activation of IFN-I and its target
genes promotes antigen-presenting cell (APC) and effector cell trafficking to the tumor bed and enhances APC
cross-priming efficiency. A central converging point of the current priming approaches is an adaptor molecule
located at the endoplasmic reticulum and its associated membranes, stimulator of interferon genes (STING).
Lead cold tumor sensitization treatments, such as irradiation, inhibition of DNA damage repair, induction of
DNA replication stress, and STING agonists all engage the STING pathway, further validating the promise of
STING-priming in restoring the immunogenicity of cancers. However, recent trials of STING agonists showed a
high resistance rate in patients with solid tumors, even in combination with ICB. The mechanism of HNC
resistance to STING priming is poorly understood, and few strategies are available to overcome cancer
resistance to innate immune sensing. The long-term goal of this program is to establish the biochemical and
metabolic regulatory network of HNC immunogenicity and improve HNC prevention and immunotherapy by
releasing the checkpoints on innate immune sensors. During the initial funding period, we have uncovered
driver oncogenes that disable the STING pathway and promote immune tolerance, we have engineered the
first-generation nanoparticles to improve the intracellular delivery of STING agonists, we have streamlined our
single-cell immune analysis pipelines to render intra-lesional immune landscape as a function of time.
Recently, we discovered a new pathway that suppresses HNC initiation through IFN-I activation. This renewal
project will parlay our previous accomplishments and our recent discovery into a cohesive program that
addresses the mechanisms of HNC resistance to STING stimulation and optimizes the engineering of a new
generation of nanoparticles for innate immune priming in hosts insensitive to free STING agonists. To support
this goal, we have established comprehensive modeling for HNC initiation and response plasticity to STING
stimulation, including carcinogen-induced models, implantable models, and genetically engineered models.
Resistance to STING stimulation disqualifies a spectrum of cold cancer priming strategies. This renewal project
will uncover a pivotal molecular mechanism underpinning the fitness of innate immune sensors and optimize
robust nanotechnology ov...

## Key facts

- **NIH application ID:** 11121513
- **Project number:** 7R01DE026728-07
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Yu Leo Lei
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $555,467
- **Award type:** 7
- **Project period:** 2024-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11121513

## Citation

> US National Institutes of Health, RePORTER application 11121513, Restoring the Immunogenicity of Head and Neck Cancer (7R01DE026728-07). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11121513. Licensed CC0.

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