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Updated: Jun 25, 2025
Macrophage Differentiation and Polarization into an M2-Like Phenotype using a Human Monocyte-Like THP-1 Leukemia Cell Line
Published on: August 2, 2021
YTHDF2 favors protumoral macrophage polarization and implies poor survival outcomes in triple negative breast cancer
Hao Jin1,2, Yue Chen1,2, Dongbo Zhang1,2
1Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province 510120, China.
Abstract:
Patients with triple-negative breast cancer (TNBC) frequently experience resistance to chemotherapy, leading to recurrence. The approach of optimizing anti-tumoral immunological effect is promising in overcoming such resistance, given the heterogeneity and lack of biomarkers in TNBC. In this study, we focused on YTHDF2, an N6-methyladenosine (m6A) RNA-reader protein, in macrophages, one of the most abundant intra-tumoral immune cells. Using single-cell sequencing and ex vivo experiments, we discovered that YTHDF2 significantly promotes pro-tumoral phenotype polarization of macrophages and is closely associated with down-regulated antigen-presentation signaling to other immune cells in TNBC. The in vitro deprivation of YTHDF2 favors anti-tumoral effect. Expressions of multiple transcription factors, especially SPI1, were consistently observed in YTHDF2-high macrophages, providing potential therapeutic targets for new strategies. In conclusion, YTHDF2 in macrophages appears to promote pro-tumoral effects while suppressing immune activity, indicating the treatment targeting YTHDF2 or its transcription factors could be a promising strategy for chemoresistant TNBC.
Insights
Targeting YTHDF2 in macrophages can overcome chemotherapy resistance in triple-negative breast cancer (TNBC). This study reveals YTHDF2 promotes pro-tumoral macrophage polarization, suggesting YTHDF2 inhibition as a novel therapeutic strategy for TNBC.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) often exhibits chemotherapy resistance and recurrence.
- Lack of specific biomarkers and tumor heterogeneity in TNBC necessitate novel therapeutic strategies.
- Macrophages are key immune cells within the tumor microenvironment, influencing cancer progression.
Purpose of the Study:
- To investigate the role of YTHDF2, an N6-methyladenosine (m6A) RNA-reader protein, in macrophages within the context of chemoresistant TNBC.
- To elucidate the impact of YTHDF2 on macrophage polarization and anti-tumoral immune responses in TNBC.
Main Methods:
- Single-cell sequencing was employed to analyze YTHDF2 expression and its correlation with macrophage phenotypes in TNBC.
- Ex vivo experiments were conducted to assess the functional consequences of YTHDF2 modulation in macrophages.
- In vitro studies were performed to evaluate the effects of YTHDF2 deprivation on anti-tumoral activity.
Main Results:
- YTHDF2 was found to significantly promote a pro-tumoral phenotype in macrophages within TNBC.
- High YTHDF2 expression in macrophages was associated with suppressed antigen-presentation signaling.
- Depriving macrophages of YTHDF2 in vitro enhanced anti-tumoral effects.
- Expression of transcription factors, notably SPI1, was linked to YTHDF2-high macrophages.
Conclusions:
- YTHDF2 in tumor-associated macrophages promotes pro-tumoral functions and dampens anti-cancer immunity in TNBC.
- Targeting YTHDF2 or its downstream transcription factors presents a promising therapeutic avenue for overcoming chemoresistance in TNBC.
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