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Cited by 68Immune cells in cancerPhagocytosis and Immune RegulationSphingolipid Metabolism and Signaling

Phosphatidylserine released from apoptotic cells in tumor induces M2‐like macrophage polarization through the PSR‐STAT3‐JMJD3 axis

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Liang, Xiao, Luo, Min, Shao, Bin, Yang, Jing‐Yun, Tong, An, Wang, Rui‐Bo, Liu, Yan‐Tong, Jun, Ren +5 more·2022·Cancer Communications
DOI 10.1002/cac2.12272PMC PMC8923121
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Abstract

Background: Understanding how the tumor microenvironment is shaped by various factors is important for the development of new therapeutic strategies. Tumor cells often undergo spontaneous apoptotic cell death in tumor microenvironment, these apoptotic cells are histologically co‐localized with immunosuppressive macrophages. However, the mechanism by which tumor cell apoptosis modulates macrophage polarization is not fully understood. In this study, we aimed to explore the tumor promoting effects of apoptotic tumor cells and the signal pathways involved. Methods: Apoptotic cells and macrophages in tumors were detected by immunohistochemical staining. Morphological analysis was performed with Giemsa staining. Lipids generated from apoptotic cells were detected by liquid chromatography‐mass spectrometry. Phosphatidylserine‐containing liposomes were prepared to mimic apoptotic cells. The expression of protein was determined by real‐time PCR, immunohistochemistry enzyme‐linked immunosorbent assay and Western blotting. Mouse malignant ascites and subcutaneous tumor models were designed for in vivo analysis. Transgenic mice with specific genes knocked out and inhibitors specific to certain proteins were used for the mechanistic studies. Results: The location and the number of apoptotic cells were correlated with that of macrophages in several types of carcinomas. Phosphatidylserine, a lipid molecule generated in apoptotic cells, induced polarization and accumulation of M2‐like macrophages in vivo and in vitro. Moreover, sustained administration of phosphoserine promoted tumor growth in the malignant ascites and subcutaneous tumor models. Further analyses suggested that phosphoserine induced a M2‐like phenotype in macrophages, which was related to the activation of phosphoserine receptors including T‐cell immunoglobin mucin 4 (TIM4) and the FAK‐SRC‐STAT3 signaling pathway as well as elevated the expression of the histone demethylase Jumonji domain‐containing protein 3 (JMJD3). Administration of specific inhibitors of these pathways could reduce tumor progression. Conclusions: This study suggest that apoptotic cell‐generated phosphoserine might be a notable signal for immunosuppressive macrophages in tumors, and the related pathways might be potential therapeutic targets for cancer therapy.

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  • In breast and lung cancers, efferocytosis is associated with tumor immune evasion and progression.

    “For instance, in breast33 and lung34 cancers, efferocytosis is associated with tumor immune evasion and progression.”

    From Macrophage efferocytosis mediated by the TP63-RAC2 pathway promotes immunosuppressive remodeling in esophageal cancer (2026) · cites this paper as [33]

    Citation 34 is attached to lung cancer, while citation 33 is attached to breast cancer. The Results report that apoptotic cells correlate with tumor-associated macrophages in human lung tumors, and the Discussion links M2-like macrophages generally to immune escape and tumor progression. The paper does not establish that efferocytosis itself is associated with immune evasion or progression specifically in lung cancer. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Liang, X., Luo, M., Shao, B., Yang, J., Tong, A., Wang, R., Liu, Y., Jun, R., Liu, T., Yi, T., Zhao, X., Wei, Y., & Wei, X.
Affiliations
  • Sichuan University (CN)
  • Sichuan University
ORCID
Venue
Cancer Communications
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-02-22
Volume
42
Issue
3
Pages
205-222
ISSN
  • 1000-467X (ISSN-L)
  • 2523-3548
DOI
10.1002/cac2.12272
PMC
PMC8923121
OpenAlex
W4213190654
Cited by
68
References
1
Citations by year
2026: 17 · 2025: 18 · 2024: 16 · 2023: 12 · 2022: 5
FWCI
4.87
Type
journal article
Language
en
Open access
Licence
Locations
  • 癌症：英文版 (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China: National Science Foundation for Excellent Young Scholars (32122052)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
Keywords
phosphatidylserine, apoptotic cells, M2 macrophages, macrophage polarization, tumor microenvironment, STAT3, JMJD3, TIM-4, FAK/Src signaling, histone demethylation, tumor immunosuppression, malignant ascites
MeSH terms
Animals, Ascites, Macrophages, Neoplasms, Phosphatidylserines, Phosphoserine, Apoptosis, STAT3 Transcription Factor, Mice, Jumonji Domain-Containing Histone Demethylases, Tumor Microenvironment

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