Cell Metabo: The team of Zhimin Shao and Yizhou Jiang found that the heterogeneity of iron death in triple-negative breast cancer may be associated with immunotherapy

On October 17, "Cell Metabolism" published the latest research
of Shao Zhimin, professor of breast surgery at Fudan University Cancer Hospital, and Jiang Yizhou's team.
The study found that "iron death" was more active in one of the subtypes of triple-negative breast cancer "Fudan classification", luminal androgen receptor type (LAR), and glutathione metabolism with "glutathione peroxidase 4" (GPX4) as the core played an important role
in the regulation of "iron death" in LAR-type triple-negative breast cancer.
The relevant research results were published
online on October 17 in Cell Metabolism (journal impact factor 31.
4), a top international journal of metabolism.
This is the third time in the past two years that the team has published a paper in this top international journal
.
GPX4 inhibitors combined with immunotherapy may be a potential new treatment strategy
for LAR-type triple-negative breast cancer.

Exploring new strategies for precision therapy from the perspective of metabolism-immunity

Triple-negative breast cancer is a member of the large family of breast cancer, and compared with other subtypes, it has high heterogeneity, poor prognosis, and high risk of recurrence and metastasis, so it has become a stubborn "fortress"
that needs to be overcome urgently in breast cancer research.
Since 2019, the team led by Professor Shao Zhimin and Professor Jiang Yizhou has carried out a series of research on triple-negative breast cancer, from the proposal of "Fudan classification" to the development of the FUTURE series of precision therapy clinical trials, the team has successfully increased the objective response rate of advanced triple-negative breast cancer patients who are ineffective with multi-line therapy from 10% to 29%, improving the prognosis
of triple-negative breast cancer patients.

However, the "Fudan classification" still needs to be improved
.
Some triple-negative breast cancers, such as the LAR molecular subtype, are less sensitive to existing precision therapy strategies and remain a treatment problem
for triple-negative breast cancer.
To this end, in recent years, the team led by Shao Zhimin and Professor Jiang Yizhou has continuously deepened the "Fudan classification" from multiple perspectives such as protein, metabolism, immunity, and microorganisms, and explored new therapeutic targets, in anticipation of breaking through the treatment bottleneck
of some subtypes of triple-negative breast cancer.

Large sample data showed the characteristics of "iron death" in triple-negative breast cancer cells

"Through the improvement of the 'Fudan classification' of triple-negative breast cancer in the early stage, we have confirmed that the treatment plan from the perspective of metabolism and immunity may bring obvious benefits
to the precision treatment of triple-negative breast cancer.
" Professor Shao Zhimin said that "iron death" is a regulatory cell death method closely related to metabolism discovered in recent years, which is active in the field of tumor research, and the team tried to start from this perspective to discover a new breakthrough in the treatment of triple-negative breast cancer
.

Among the "pattern death" of cells, "iron death" is one of them, because this form of death is driven by "iron-dependent lipid peroxidation" and is regulated
by multiple metabolic pathways.
Through the study of large transcriptome and metabolomic data, the team first systematically analyzed the characteristics of iron death in
triple-negative breast cancer.

The study found that the cellular metabolic pathways and metabolites associated with "iron death" were highly active in LAR breast cancer, suggesting that it may be the most sensitive subtype
to "iron death".
On the other hand, glutathione metabolism with GPX4 as the core is significantly upregulated in the LAR subtype, which is the most important way
for tumors of this subtype to escape "iron death".

Through further mechanisms, the researchers found that androgen receptors (AR) are key factors
in regulating iron death of the LAR subtype.
However, the regulatory effect of AR on "iron death" in triple-negative breast cancer is positive and negative, which can not only promote the expression of GPX4 to assist tumor cells to escape "iron death", but also increase the synthesis
of unsaturated lipids related to "iron death".
This may partly explain the poor efficacy of AR receptor inhibitors in clinical trials for LAR breast cancer
.

GPX4 inhibitors combined with immunotherapy may become new therapeutic targets

The team further utilized mouse models, organoid models, and retrospective clinical trial data to explore the clinical value
of targeting "iron death" in the LAR subtype.
The results showed that GPX4 inhibitors could not only inhibit tumors by promoting "iron death", but also reshape the tumor immune microenvironment, making LAR subtype tumors "cold" to "hot"
.
GPX4 inhibitors in combination with immunotherapy can further activate T cells in the tumor microenvironment, and the efficacy of dual-agent therapy is significantly higher than that of monotherapy
.
This result shows that the combination of targeted iron death and immunotherapy may be a new direction
for precision therapy of LAR subtype breast cancer.

"This study is a further expansion of our triple-negative breast cancer research system, and the research model is also very novel.
"
Professor Jiang Yizhou said that the study starts from key clinical problems, selects novel angles, makes full use of multi-omics data, combines solid experimental demonstration, and finally returns to clinical treatment
.

"Focusing on key clinical science issues and conducting research that is truly useful to patients is what Professor Shao has always asked
of us.
" Dr.
Xiao Yi said, "As a young generation, we are fortunate to stand on the shoulders of giants and continuously expand the depth and breadth of precision treatment for triple-negative breast cancer, hoping to bring good news
to more patients.
" ”

Original source:

https://doi.
org/10.
1016/j.
cmet.
2022.
09.
021