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Cited by 80Immune cells in cancerPhagocytosis and Immune RegulationImmunotherapy and Immune Responses

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Thymosin α-1 Reverses M2 Polarization of Tumor-Associated Macrophages during Efferocytosis

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Wei, Yi-ting, Wang, Xu-ru, Yan, Chunguang, Huang, Fang, Zhang, Yunpeng, Liu, Xueming, Wen, Zhi-fa, Sun, Xiao-tong, Zhang, Yue, Chen, Yong-qiang, Gao, Rong, Pan, Ning, Wang, Li-xin·2022·Cancer Research
DOI 10.1158/0008-5472.can-21-4260

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Abstract

The immunologic effects of chemotherapy-induced tumor cell death are not completely understood. Accumulating evidence suggests that phagocytic clearance of apoptotic tumor cells, also known as efferocytosis, is an immunologically silent process, thus maintaining an immunosuppressive tumor microenvironment (TME). Here we report that, in the breast tumor microenvironment, thymosin α-1 (Tα-1) significantly reverses M2 polarization of IL10-producing tumor-associated macrophages (TAM) during efferocytosis induced by apoptotic cells. Mechanistically, Tα-1, which bound to phosphatidylserine on the surface of apoptotic tumor cells and was internalized by macrophages, triggered the activation of SH2-containing inositol 5′-phosphatase 1 (SHIP1) through the lysosomal Toll-like receptor 7 (TLR7)/MyD88 pathway, subsequently resulting in dephosphorylation of efferocytosis-activated TBK1 and reduction of efferocytosis-induced IL10. Tα-1 combined with epirubicin chemotherapy markedly suppressed tumor growth in an in vivo breast cancer model by reducing macrophage-derived IL10 and enhancing the number and function of tumor-infiltrating CD4+ and CD8+ T cells. In conclusion, Tα-1 improved the curative effect of chemotherapy by reversing M2 polarization of efferocytosis-activated macrophages, suggesting that Tα-1 injection immediately after chemotherapy may contribute to highly synergistic antitumor effects in patients with breast cancer. Significance: Thymosin α-1 improves the curative effect of chemotherapy by reversing efferocytosis-induced M2 polarization of macrophages via activation of a TLR7/SHIP1 axis.

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  • Impaired efferocytosis reduces TAM recognition and engulfment of tumor cells, compromising immune surveillance and contributing to resistance to antitumor therapies.

    “Impaired efferocytosis reduces TAM recognition and engulfment of tumor cells, compromising immune surveillance and contributing to resistance to antitumor therapies.”

    From Macrophage efferocytosis mediated by the TP63-RAC2 pathway promotes immunosuppressive remodeling in esophageal cancer (2026) · cites this paper as [15]

    The Introduction identifies efferocytosis as the removal of apoptotic tumor cells by phagocytes, including TAMs, and says directly impairing it can cause secondary necrosis and drive tumor progression. It does not say impaired efferocytosis compromises immune surveillance or causes resistance to antitumor therapies; instead, it describes chemotherapy-induced efferocytosis as promoting an immunosuppressive TAM phenotype. (LLM, conf=0.85)

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Metadata

Authors
Wei, Y.-T., Wang, X.-R., Yan, C., Huang, F., Zhang, Y., Liu, X., Wen, Z.-F., Sun, X.-T., Zhang, Y., Chen, Y.-Q., Gao, R., Pan, N., & Wang, L.-X.
Affiliations
Southeast University (CN)
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2022-04-01
Volume
82
Issue
10
Pages
1991-2002
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-21-4260
OpenAlex
W4226326695
Cited by
80
References
3
Citations by year
2026: 23 · 2025: 25 · 2024: 21 · 2023: 9 · 2022: 2
FWCI
5.44
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (31670918, 31970849)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
thymosin alpha 1, efferocytosis, tumor-associated macrophages, M2 macrophage polarization, IL-10, breast cancer, tumor microenvironment, SHIP1, epirubicin, phosphatidylserine, tumor-infiltrating T cells, immunosuppression
MeSH terms
Thymalfasin, Tumor-Associated Macrophages, Breast Neoplasms, Female, Humans, Interleukin-10, Toll-Like Receptor 7, Tumor Microenvironment

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