*Result*: Single-cell transcriptome analysis reveals macrophage-specific apolipoprotein C1 as a key regulator of polarization and progression in triple-negative breast cancer.
Title:
Single-cell transcriptome analysis reveals macrophage-specific apolipoprotein C1 as a key regulator of polarization and progression in triple-negative breast cancer.
Authors:
Xu M; Department of Radiotherapy, Changji Hui Autonomous Prefecture People's Hospital, Changji City, Xinjiang Province, China., Jin H; Department of Radiation Oncology, Linquan County People's Hospital, Linquan County, Anhui Province, China., Yang F; Department of Radiotherapy, Changji Hui Autonomous Prefecture People's Hospital, Changji City, Xinjiang Province, China., Yang P; Department of Radiotherapy, Changji Hui Autonomous Prefecture People's Hospital, Changji City, Xinjiang Province, China., Wu Q; Department of Oncology, Changji Hui Autonomous Prefecture People's Hospital, Changji City, Xinjiang Province, China.
Source:
Immunology and cell biology [Immunol Cell Biol] 2026 Jan; Vol. 104 (1), pp. 54-66. Date of Electronic Publication: 2025 Nov 26.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Wiley Country of Publication: United States NLM ID: 8706300 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1440-1711 (Electronic) Linking ISSN: 08189641 NLM ISO Abbreviation: Immunol Cell Biol Subsets: MEDLINE
Imprint Name(s):
Publication: 2018- : [Hoboken, NJ] : Wiley
Original Publication: [Adelaide, South Australia] : University of Adelaide, [c1987-
Original Publication: [Adelaide, South Australia] : University of Adelaide, [c1987-
MeSH Terms:
Triple Negative Breast Neoplasms*/pathology , Triple Negative Breast Neoplasms*/genetics , Triple Negative Breast Neoplasms*/immunology , Triple Negative Breast Neoplasms*/metabolism , Apolipoprotein C-I*/metabolism , Apolipoprotein C-I*/genetics , Macrophages*/metabolism , Tumor-Associated Macrophages*/metabolism , Tumor-Associated Macrophages*/immunology , Single-Cell Analysis*, Humans ; Female ; Disease Progression ; Gene Expression Profiling ; Cell Line, Tumor ; Transcriptome ; Cell Proliferation ; Cell Movement ; Animals ; Gene Expression Regulation, Neoplastic ; Mice ; Single-Cell Gene Expression Analysis
References:
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Leon‐Ferre RA, Goetz MP. Advances in systemic therapies for triple negative breast cancer. BMJ 2023; 381: e071674.
Li Y, Zhang H, Merkher Y, et al. Recent advances in therapeutic strategies for triple‐negative breast cancer. J Hematol Oncol 2022; 15: 121.
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Xiang X, Wang J, Lu D, Xu X. Targeting tumor‐associated macrophages to synergize tumor immunotherapy. Signal Transduct Target Ther 2021; 6: 75.
Liu J, Cao X. Glucose metabolism of TAMs in tumor chemoresistance and metastasis. Trends Cell Biol 2023; 33: 967–978.
Chu X, Tian Y, Lv C. Decoding the spatiotemporal heterogeneity of tumor‐associated macrophages. Mol Cancer 2024; 23: 150.
Han S, Bao X, Zou Y, et al. d‐lactate modulates M2 tumor‐associated macrophages and remodels immunosuppressive tumor microenvironment for hepatocellular carcinoma. Sci Adv 2023; 9: eadg2697.
Li Y, Han X, Lin Z, et al. G6PD activation in TNBC cells induces macrophage recruitment and M2 polarization to promote tumor progression. Cell Mol Life Sci 2023; 80: 165.
Tang W, Liu H, Li X, et al. Upregulation of APOC1 promotes colorectal cancer progression and serves as a potential therapeutic target based on bioinformatics analysis. J Oncol 2023; 2023: 2611105.
Shi X, Wang J, Dai S, Qin L, Zhou J, Chen Y. Apolipoprotein C1 (APOC1): a novel diagnostic and prognostic biomarker for cervical cancer. Onco Targets Ther 2020; 13: 12881–12891.
Zheng XJ, Chen WL, Yi J, et al. Apolipoprotein C1 promotes glioblastoma tumorigenesis by reducing KEAP1/NRF2 and CBS‐regulated ferroptosis. Acta Pharmacol Sin 2022; 43: 2977–2992.
Xu H, Ba Z, Liu C, Yu X. Long noncoding RNA DLEU1 promotes proliferation and glycolysis of gastric cancer cells via APOC1 upregulation by recruiting SMYD2 to induce trimethylation of H3K4 modification. Transl Oncol 2023; 36: 101731.
Ren L, Yi J, Yang Y, et al. Systematic pan‐cancer analysis identifies APOC1 as an immunological biomarker which regulates macrophage polarization and promotes tumor metastasis. Pharmacol Res 2022; 183: 106376.
Hao X, Zheng Z, Liu H, et al. Inhibition of APOC1 promotes the transformation of M2 into M1 macrophages via the ferroptosis pathway and enhances anti‐PD1 immunotherapy in hepatocellular carcinoma based on single‐cell RNA sequencing. Redox Biol 2022; 56: 102463.
Li M, Yang Y, Xiong L, Jiang P, Wang J, Li C. Metabolism, metabolites, and macrophages in cancer. J Hematol Oncol 2023; 16: 80.
Lahmar Q, Keirsse J, Laoui D, Movahedi K, Van Overmeire E, Van Ginderachter JA. Tissue‐resident versus monocyte‐derived macrophages in the tumor microenvironment. Biochim Biophys Acta 2016; 1865: 23–34.
Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell 2015; 27: 462–472.
Cheng K, Cai N, Zhu J, Yang X, Liang H, Zhang W. Tumor‐associated macrophages in liver cancer: from mechanisms to therapy. Cancer Commun (Lond) 2022; 42: 1112–1140.
van Vlerken‐Ysla L, Tyurina YY, Kagan VE, Gabrilovich DI. Functional states of myeloid cells in cancer. Cancer Cell 2023; 41: 490–504.
Barry ST, Gabrilovich DI, Sansom OJ, Campbell AD, Morton JP. Therapeutic targeting of tumour myeloid cells. Nat Rev Cancer 2023; 23: 216–237.
Bashant KR, Toepfner N, Day CJ, et al. The mechanics of myeloid cells. Biol Cell 2020; 112: 103–112.
Timperi E, Gueguen P, Molgora M, et al. Lipid‐associated macrophages are induced by cancer‐associated fibroblasts and mediate immune suppression in breast cancer. Cancer Res 2022; 82: 3291–3306.
Huang Y, Mahley RW. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases. Neurobiol Dis 2014; 72(Pt A): 3–12.
Mahley RW. Central nervous system lipoproteins: ApoE and regulation of cholesterol metabolism. Arterioscler Thromb Vasc Biol 2016; 36: 1305–1315.
Liguori M, Digifico E, Vacchini A, et al. The soluble glycoprotein NMB (GPNMB) produced by macrophages induces cancer stemness and metastasis via CD44 and IL‐33. Cell Mol Immunol 2021; 18: 711–722.
Lazaratos AM, Annis MG, Siegel PM. GPNMB: a potent inducer of immunosuppression in cancer. Oncogene 2022; 41: 4573–4590.
Meng Y, Zhao Q, Sang Y, et al. GPNMB(+) Gal‐3(+) hepatic parenchymal cells promote immunosuppression and hepatocellular carcinogenesis. EMBO J 2023; 42: e114060.
Ma RY, Black A, Qian BZ. Macrophage diversity in cancer revisited in the era of single‐cell omics. Trends Immunol 2022; 43: 546–563.
Leon‐Ferre RA, Goetz MP. Advances in systemic therapies for triple negative breast cancer. BMJ 2023; 381: e071674.
Li Y, Zhang H, Merkher Y, et al. Recent advances in therapeutic strategies for triple‐negative breast cancer. J Hematol Oncol 2022; 15: 121.
Bai X, Ni J, Beretov J, Graham P, Li Y. Triple‐negative breast cancer therapeutic resistance: where is the Achilles' heel? Cancer Lett 2021; 497: 100–111.
Xiao Y, Yu D. Tumor microenvironment as a therapeutic target in cancer. Pharmacol Ther 2021; 221: 107753.
Vitale I, Manic G, Coussens LM, Kroemer G, Galluzzi L. Macrophages and metabolism in the tumor microenvironment. Cell Metab 2019; 30: 36–50.
Chen D, Zhang X, Li Z, Zhu B. Metabolic regulatory crosstalk between tumor microenvironment and tumor‐associated macrophages. Theranostics 2021; 11: 1016–1030.
Xiang X, Wang J, Lu D, Xu X. Targeting tumor‐associated macrophages to synergize tumor immunotherapy. Signal Transduct Target Ther 2021; 6: 75.
Liu J, Cao X. Glucose metabolism of TAMs in tumor chemoresistance and metastasis. Trends Cell Biol 2023; 33: 967–978.
Chu X, Tian Y, Lv C. Decoding the spatiotemporal heterogeneity of tumor‐associated macrophages. Mol Cancer 2024; 23: 150.
Han S, Bao X, Zou Y, et al. d‐lactate modulates M2 tumor‐associated macrophages and remodels immunosuppressive tumor microenvironment for hepatocellular carcinoma. Sci Adv 2023; 9: eadg2697.
Li Y, Han X, Lin Z, et al. G6PD activation in TNBC cells induces macrophage recruitment and M2 polarization to promote tumor progression. Cell Mol Life Sci 2023; 80: 165.
Tang W, Liu H, Li X, et al. Upregulation of APOC1 promotes colorectal cancer progression and serves as a potential therapeutic target based on bioinformatics analysis. J Oncol 2023; 2023: 2611105.
Shi X, Wang J, Dai S, Qin L, Zhou J, Chen Y. Apolipoprotein C1 (APOC1): a novel diagnostic and prognostic biomarker for cervical cancer. Onco Targets Ther 2020; 13: 12881–12891.
Zheng XJ, Chen WL, Yi J, et al. Apolipoprotein C1 promotes glioblastoma tumorigenesis by reducing KEAP1/NRF2 and CBS‐regulated ferroptosis. Acta Pharmacol Sin 2022; 43: 2977–2992.
Xu H, Ba Z, Liu C, Yu X. Long noncoding RNA DLEU1 promotes proliferation and glycolysis of gastric cancer cells via APOC1 upregulation by recruiting SMYD2 to induce trimethylation of H3K4 modification. Transl Oncol 2023; 36: 101731.
Ren L, Yi J, Yang Y, et al. Systematic pan‐cancer analysis identifies APOC1 as an immunological biomarker which regulates macrophage polarization and promotes tumor metastasis. Pharmacol Res 2022; 183: 106376.
Hao X, Zheng Z, Liu H, et al. Inhibition of APOC1 promotes the transformation of M2 into M1 macrophages via the ferroptosis pathway and enhances anti‐PD1 immunotherapy in hepatocellular carcinoma based on single‐cell RNA sequencing. Redox Biol 2022; 56: 102463.
Li M, Yang Y, Xiong L, Jiang P, Wang J, Li C. Metabolism, metabolites, and macrophages in cancer. J Hematol Oncol 2023; 16: 80.
Lahmar Q, Keirsse J, Laoui D, Movahedi K, Van Overmeire E, Van Ginderachter JA. Tissue‐resident versus monocyte‐derived macrophages in the tumor microenvironment. Biochim Biophys Acta 2016; 1865: 23–34.
Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell 2015; 27: 462–472.
Cheng K, Cai N, Zhu J, Yang X, Liang H, Zhang W. Tumor‐associated macrophages in liver cancer: from mechanisms to therapy. Cancer Commun (Lond) 2022; 42: 1112–1140.
van Vlerken‐Ysla L, Tyurina YY, Kagan VE, Gabrilovich DI. Functional states of myeloid cells in cancer. Cancer Cell 2023; 41: 490–504.
Barry ST, Gabrilovich DI, Sansom OJ, Campbell AD, Morton JP. Therapeutic targeting of tumour myeloid cells. Nat Rev Cancer 2023; 23: 216–237.
Bashant KR, Toepfner N, Day CJ, et al. The mechanics of myeloid cells. Biol Cell 2020; 112: 103–112.
Timperi E, Gueguen P, Molgora M, et al. Lipid‐associated macrophages are induced by cancer‐associated fibroblasts and mediate immune suppression in breast cancer. Cancer Res 2022; 82: 3291–3306.
Huang Y, Mahley RW. Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases. Neurobiol Dis 2014; 72(Pt A): 3–12.
Mahley RW. Central nervous system lipoproteins: ApoE and regulation of cholesterol metabolism. Arterioscler Thromb Vasc Biol 2016; 36: 1305–1315.
Liguori M, Digifico E, Vacchini A, et al. The soluble glycoprotein NMB (GPNMB) produced by macrophages induces cancer stemness and metastasis via CD44 and IL‐33. Cell Mol Immunol 2021; 18: 711–722.
Lazaratos AM, Annis MG, Siegel PM. GPNMB: a potent inducer of immunosuppression in cancer. Oncogene 2022; 41: 4573–4590.
Meng Y, Zhao Q, Sang Y, et al. GPNMB(+) Gal‐3(+) hepatic parenchymal cells promote immunosuppression and hepatocellular carcinogenesis. EMBO J 2023; 42: e114060.
Ma RY, Black A, Qian BZ. Macrophage diversity in cancer revisited in the era of single‐cell omics. Trends Immunol 2022; 43: 546–563.
Grant Information:
2022 Xinjiang Uygur Autonomous Region "Tianchi talents" Introduction Plan
Contributed Indexing:
Keywords: Apolipoprotein C1; glycolysis; macrophages; single‐cell transcriptome analysis; triple‐negative breast cancer
Substance Nomenclature:
0 (Apolipoprotein C-I)
0 (APOC1 protein, human)
0 (APOC1 protein, human)
Entry Date(s):
Date Created: 20251126 Date Completed: 20260114 Latest Revision: 20260114
Update Code:
20260130
DOI:
10.1111/imcb.70066
PMID:
41294154
Database:
MEDLINE
*Further Information*
*Tumor-associated macrophages (TAMs) play critical roles in the progression of triple-negative breast cancer (TNBC), yet the mechanisms underlying their differentiation remain unclear. Heterogeneity of macrophages in TNBC tissues was comprehensively dissected using single-cell transcriptome analysis. The crucial role of Apolipoprotein C1 (APOC1) in macrophages was investigated through loss or gain-of-function experiments. Single-cell analysis revealed that myeloid cells were the second most metabolically active cell type in TNBC after epithelial cells, with a subset of lipid-associated macrophages (LA-TAMs) potentially linked to TNBC progression. Further analysis showed significant upregulation of APOC1 in myeloid cells and LA-TAMs, with pseudo-temporal expression profiling indicating that APOC1 tended to be expressed in the mid-late stages of macrophage development. KEGG analysis highlighted significant enrichment of APOC1 in glycolysis-related pathways. Cell experiments in vitro demonstrated that macrophages overexpressing APOC1 exhibited enhanced glycolytic activity, a skew toward an immunosuppressive M2 phenotype, and increased secretion of anti-inflammatory cytokines. APOC1-deficient macrophages effectively slowed the progression of TNBC by suppressing the proliferation, migration, and invasion of TNBC cells. These findings suggested that APOC1 promoted macrophage polarization toward the pro-tumor M2 phenotype by activating the glycolytic pathway, thereby facilitating the malignant progression of TNBC. This study provides new insights into the role of macrophages in TNBC and establishes a theoretical basis for developing immunotherapeutic strategies targeting APOC1.
(© 2025 the Australian and New Zealand Society for Immunology, Inc.)*