Single‐cell transcriptome analysis reveals macrophage‐specific apolipoprotein C1 as a key regulator of polarization and progression in triple‐negative breast cancer

Abstract 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.