TY  - EJOU
AU  - Hong, Chang-Eui 
AU  - Lyu, Su-Yun 

TI  - Mistletoe Lectin Overcomes Macrophage-Mediated Chemo-Resistance in 3D Co-Culture Models of Triple-Negative Breast Cancer
T2  - BIOCELL

PY  - 2026
VL  - 50
IS  - 2
SN  - 1667-5746

AB  -  <b>Objective:</b> Tumor-associated macrophages (TAMs) contribute to chemoresistance in triple-negative breast cancer (TNBC), yet strategies to reprogram TAMs while enhancing chemotherapy efficacy remain limited. This study investigated whether <i>Viscum album</i> L. var. <i>coloratum</i> agglutinin (VCA) could sensitize TNBC cells to doxorubicin (DOX) and modulate TAM-mediated chemoresistance in three-dimensional (3D) co-culture models. <b>Methods:</b> MDA-MB-231 TNBC cells were co-cultured with RAW264.7 macrophages in collagen-embedded 3D spheroids. Spheroid viability was assessed using an ATP-based luminescent assay. Cytokine secretion and epithelial-mesenchymal transition (EMT) markers were measured using ELISA and Western blotting. Drug synergy was evaluated using combination index (CI) calculations. <b>Results:</b> VCA-DOX combination demonstrated synergistic cytotoxicity exclusively in co-culture spheroids (CI = 0.72), reducing viability to 25.9% (<i>p</i> < 0.001), while showing no synergy in monoculture (CI = 1.52). Combination treatment decreased VEGF secretion by 49% and IL-6 by 74%, while elevating TNF-α 2.7-fold, suggesting macrophage reprogramming. VCA enhanced E-cadherin expression while suppressing mesenchymal markers in co-culture spheroids and reduced Matrigel invasion by 60% (<i>p</i> < 0.001). <b>Conclusion:</b> VCA-DOX combination demonstrates synergistic anticancer effects through TAM reprogramming and enhanced chemosensitization specifically in 3D co-culture models, warranting further investigation for overcoming macrophage-mediated chemoresistance in TNBC.
KW  - Korean mistletoe lectin; triple-negative breast cancer; doxorubicin; combination therapy

DO  - 10.32604/biocell.2025.075574