# Re-engineering differential regulation of ferroptosis in melanoma microenvironment

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $642,352

## Abstract

Project Summary
Melanoma is an aggressive and highly metastatic skin cancer. Although modern combination checkpoint
inhibitors revolutionized clinical outcomes in advanced cases, over half of all patients are refractory to
immunotherapy and require alternative or complementary treatment options. The discovery of ferroptosis
provided a novel way to treat cancer. Recently described vulnerability of melanoma cells to ferroptosis offers
a new therapeutic opportunity, particularly against the malignant cells which are resistant to current therapies.
However, how to exploit such vulnerability is still unclear due to the lack of mechanistic understanding of
ferroptosis regulation in melanoma and the tumor-infiltrating immune cells. We discovered that an
indiscriminate induction of ferroptosis of the entire tumor tissue has a deleterious impact on protective anti-
tumor immune responses, which promotes melanoma progression. Specifically, we found that ferroptotic
death of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in tumors is a major mechanism
of immune suppression. Therefore, a shift in the current approach to harness ferroptosis for cancer therapy
is required. Only by understanding the regulatory mechanisms of ferroptosis in different cellular compartments
of the tumor microenvironment (TME) will we be able to engineer effective melanoma therapy based on the
differential modulation of ferroptosis. Utilizing cutting-edge redox lipidomics mass spectrometry and single-
cell lipidomics imaging methods, this project will uncover critical mechanisms of ferroptosis regulation in the
intratumoral PMN-MDSC and melanoma cells. In addition, we will optimize our recently developed therapeutic
approach which will promote ferroptosis of the malignant cells while protecting and enhancing anti-tumor
immunity. To achieve these goals, we will pursue three specific aims. In Aim 1, we will decipher how the
processes of melanogenesis and cell differentiation regulate melanoma cell susceptibility to ferroptosis. The
results will provide a strategic approach to maximizing the efficacy of pro-ferroptotic therapy against
melanoma cells. Aim 2 will focus on identifying mechanisms of ferroptosis-mediated immune regulation by
PMN-MDSC in melanoma TME. The results will reveal how to protect anti-tumor immune responses via
targeted ferroptosis inhibition in the myeloid cells of the TME and prevent immune tolerance to cancer. Finally,
in Aim 3 we will expand on our preliminary data to investigate therapeutic potential of differentially regulating
ferroptosis in the malignant and the myeloid cells of the melanoma TME. This will be accomplished using our
previously developed nano-delivery systems based on graphene quantum nanodots and carbon nanotubes.
Such approach is highly clinically relevant as it employs both cytotoxic and immunomodulatory strategies
against melanoma aimed at reducing immune tolerance to cancer and overcoming modes of cancer
resistance to the ...

## Key facts

- **NIH application ID:** 10886799
- **Project number:** 5R01CA272946-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Yuri Bunimovich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $642,352
- **Award type:** 5
- **Project period:** 2023-07-12 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886799

## Citation

> US National Institutes of Health, RePORTER application 10886799, Re-engineering differential regulation of ferroptosis in melanoma microenvironment (5R01CA272946-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10886799. Licensed CC0.

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