Single-cell transcriptome analysis reveals macrophage-specific apolipoprotein C1 as a key regulator of polarization...

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.