Cited by 64Phagocytosis and Immune RegulationImmune cells in cancerCell death mechanisms and regulation

The complex roles of efferocytosis in cancer development, metastasis, and treatment

Open access
Tajbakhsh, Amir, Gheibi hayat, Seyed Mohammad, Movahedpour, Ahmad, Savardashtaki, Amir, Loveless, Reid, Barreto, George E., Teng, Yong, Sahebkar, Amirhossein·2021·Biomedicine & Pharmacotherapy

Abstract

When tumor cells are killed by targeted therapy, radiotherapy, or chemotherapy, they trigger their primary tumor by releasing pro-inflammatory cytokines. Microenvironmental interactions can also promote tumor heterogeneity and development. In this line, several immune cells within the tumor microenvironment, including macrophages, dendritic cells, regulatory T-cells, and CD8+ and CD4+ T cells, are involved in the clearance of apoptotic tumor cells through a process called efferocytosis. Although the efficiency of apoptotic tumor cell efferocytosis is positive under physiological conditions, there are controversies regarding its usefulness in treatment-induced apoptotic tumor cells (ATCs). Efferocytosis can show the limitation of cytotoxic treatments, such as chemotherapy and radiotherapy. Since cytotoxic treatments lead to extensive cell mortality, efferocytosis, and macrophage polarization toward an M2 phenotype, the immune response may get involved in tumor recurrence and metastasis. Tumor cells can use the anti-inflammatory effect of apoptotic tumor cell efferocytosis to induce an immunosuppressive condition that is tumor-tolerant. Since M2 polarization and efferocytosis are tumor-promoting processes, the receptors on macrophages act as potential targets for cancer therapy. Moreover, researchers have shown that efferocytosis-related molecules/pathways are potential targets for cancer therapy. These include phosphatidylserine and calreticulin, Tyro3, Axl, and Mer tyrosine kinase (MerTK), receptors of tyrosine kinase, indoleamine-2,3-dioxygenase 1, annexin V, CD47, TGF-β, IL-10, and macrophage phenotype switch are combined with conventional therapy, which can be more effective in cancer treatment. Thus, we set out to investigate the advantages and disadvantages of efferocytosis in treatment-induced apoptotic tumor cells.

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Crossref · 10.1016/j.biopha.2021.111776

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  • Cancer cells are known to stimulate efferocytotic pathways.

    “The effects were more pronounced when using apoptotic neutrophils as bait compared to cancer cells, perhaps because cancer cells are known to stimulate efferocytotic pathways (68).”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [68]

    The Abstract describes efferocytosis of apoptotic tumor cells, and section 2.3.5 discusses tumor-cell molecules involved in their engulfment. This supports the claim for apoptotic cancer cells, but the cited paper does not establish that cancer cells generally stimulate efferocytotic pathways; section 2 also notes that tumor-cell CD47 can inhibit recognition by immune cells. No page numbers were supplied for these passages. (LLM, conf=0.82)

    Experimental — accuracy not yet measured
  • Efferocytosis plays a significant role in other cancer types as well.

    “Although this study focuses on ESCC, efferocytosis plays a significant role in other cancer types as well.32”

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Authors
Tajbakhsh, A., Gheibi hayat, S. M., Movahedpour, A., Savardashtaki, A., Loveless, R., Barreto, G. E., Teng, Y., & Sahebkar, A.
Affiliations
  • Shiraz University of Medical Sciences (IR)
  • Augusta University (US)
  • University of Limerick (IE)
  • Mashhad University of Medical Sciences (IR)
Corresponding author
  • Savardashtaki, Amir
  • Sahebkar, Amirhossein
Venue
Biomedicine & Pharmacotherapy
Publisher
Elsevier BV
Published
2021-08
Volume
140
Pages
111776
ISSN
0753-3322 (ISSN-L)
OpenAlex
W3164646445
Cited by
64
References
200
Citations by year
2026: 13 · 2025: 15 · 2024: 16 · 2023: 13 · 2022: 6 · 2021: 1
FWCI
0.92
Type
journal article
Language
en
Open access
Locations
  • Biomedicine & Pharmacotherapy (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Limerick Institutional Repository (University of Limerick) (acceptedVersion, cc-by-nc-sa)
  • University of Limerick Institutional Repository (University of Limerick) (acceptedVersion, other-oa)
  • Arrow@dit (Dublin Institute of Technology) (submittedVersion, cc-by-nc-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by-nc-sa)
  • University of Limerick Institutional Repository (University of Limerick)
Funders
  • Shiraz University of Medical Sciences
  • Shiraz University
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
efferocytosis, apoptotic tumor cells, tumor microenvironment, macrophage polarization, M2 macrophages, tumor immunosuppression, tumor heterogeneity, metastasis, tumor recurrence, CD47, phosphatidylserine, calreticulin, receptor tyrosine kinase, IDO1, annexin V, TGF-beta, IL-10, combination cancer therapy
MeSH terms
Animals, Endocytosis, Humans, Neoplasms, Apoptosis

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