# Targeting mitochondrial vulnerabilities to drive intrinsic melanoma immunogenicity

> **NIH NIH K99** · DANA-FARBER CANCER INST · 2024 · $128,798

## Abstract

Project Summary: Immunotherapies have revolutionized the clinical treatment of melanoma; however, these
treatment strategies have been ineffective in treating late stage and metastatic melanoma lesions with overall
patient response rates below 50% illustrating an unmet medical need in melanoma therapy.
We have previously demonstrated that mitochondrial metabolism played an important role in melanoma
metastasis and hence, I sought to investigate the role of mitochondria in facilitating this aggressive form of the
disease. Interestingly, our preliminary results indicate that specific deletion of mitochondrial complex I subunit
Ndufs4 in tumor cells led to a dramatic anti-tumor immune response. Proteomic and metabolomic analyses of
the tumor samples reveal that mitochondrial complex I inhibition induces an upregulation of proteins involved in
antigen presentation, and a shift of choline metabolism from choline-sarcosine pathway to choline-
phosphatidylcholine pathway. Tumor-Infiltrating Lymphocytes (TIL) analyses reveal a significant increase of NKT
cells. However, the mechanisms by which mitochondrial complex I inhibition induces antigen presentation,
metabolic flux shift and NKT cell activation are still waiting to be explored.
Based on our encouraging preliminary results, I seek to further explore the mechanisms whereby mitochondrial
complex I activity in tumor cells modulates immune response in tumor microenvironment by focusing on three
Aims. In Aim-1, I will determine the mechanisms of how mitochondrial complex I inhibition enhances MHC-I
dependent antigen presentation. In Aim-2, I plan to determine the mechanisms whereby mitochondrial complex
I inhibition causes the metabolic shift, choline-betaine to choline-phosphatidylcholine, and its potential roles in
NKT cell recruitment and activation. Finally, in Aim-3 I will evaluate the efficacy of combination treatment of
immune checkpoint inhibitors with mitochondrial complex I inhibition in preclinical mouse melanoma models.
While Aims 1 and part of 2 will be completed during the training stage, part of Aim 2 and the entire Aim 3 will be
conducted during the independent phase of the award.
The extensive training in different fields proposed in this application including proteomics, metabolomics and
immunology will provide the tools to for me to become an independent researcher and study the mechanisms of
which mitochondrial complex I regulates immune response in the tumor microenvironment. This training will be
received in the vibrant scientific communities of Dana-Farber Cancer Institute and Harvard Medical School. This
environment will expose me to the collaborations and discussions necessary for career development and future
opportunities. Dr. Puigserver mentorship will be supportive to establish those connections and actively guide me
in talk and manuscript preparation, student mentorship, experimental design, and career development. Together,
the research and career development plans propose...

## Key facts

- **NIH application ID:** 10886232
- **Project number:** 1K99CA283154-01A1
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Jiaxin Liang
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $128,798
- **Award type:** 1
- **Project period:** 2024-04-04 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886232

## Citation

> US National Institutes of Health, RePORTER application 10886232, Targeting mitochondrial vulnerabilities to drive intrinsic melanoma immunogenicity (1K99CA283154-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10886232. Licensed CC0.

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