The complex roles of efferocytosis in cancer development, metastasis, and treatment
Open accessAbstract
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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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 measuredEfferocytosis 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”
From Macrophage efferocytosis mediated by the TP63-RAC2 pathway promotes immunosuppressive remodeling in esophageal cancer (2026) · cites this paper as [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
- ORCID
- 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
- gold
- doi.org
- Licence
- 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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