Abstract
The urgent need for novel therapeutic strategies in triple-negative breast cancer (TNBC)-characterized by absent ER, PR, and HER2 expression-stems from its association with a paucity of effective treatments and an adverse prognosis. This study identifies TNFRSF12A as a key gene specifically overexpressed in TNBC versus other subtypes. Validation with clinical specimens confirmed its exclusive upregulation in TNBC tissues, correlating significantly with worse patient outcomes. Functional enrichment analysis (STRING/DAVID) indicated TNFRSF12A's primary involvement in pathways positively regulating cell migration, angiogenesis, and hypoxia response. Immune infiltration profiling (TIMER/TISCH2) revealed selective enrichment of TNFRSF12A in cancer-associated fibroblasts (CAFs). Its expression showed a significant positive correlation with the CAF marker FAP (ρ = 0.304) and CAF infiltration levels, but inverse correlations with CD8(+) T-cell (Cor = -0.165) and B-cell (Cor = -0.164) infiltration. Regarding chemoresistance, elevated TNFRSF12A expression significantly increased sensitivity to docetaxel. Molecular docking simulations further verified direct binding between TNFRSF12A and docetaxel, mediated by hydrophobic interactions and hydrogen bonds. To elucidate the underlying molecular mechanisms, cellular experiments revealed that TNFRSF12A knockdown resulted in (1) significantly compromised angiogenic capacity in HUVEC tube formation assays (p < 0.01); (2) markedly augmented cytotoxicity of T cells against tumor cells (p < 0.05); and (3) reduced cellular sensitivity to docetaxel, as evidenced by significantly elevated IC(50) values in CCK-8 assays (p < 0.01). In summary, this study systematically elucidates how TNFRSF12A propels TNBC malignant progression by remodeling the tumor immune microenvironment and promoting angiogenesis. Concurrently, we reveal a TNFRSF12A-mediated chemosensitizing effect towards docetaxel. Therefore, these results are crucial for improving the targeting of TNFRSF12A and developing precise combination treatment regimens to improve outcomes for patients with TNBC.