Fast-Food Component-Induced Epigenetic Modifications Modulate Immunotherapy in Metastatic Breast Cancer.

The impact of fast-food components on epigenetic modifications and their implications for immunotherapy in metastatic breast cancer remain inadequately explored. In this study, we investigated the effects of selected fast-food components monosodium glutamate (MSG), acrylamide (AA), sodium sorbate (SS), and sodium nitrite (NaNO2) on the expression of the epigenetic enzymes histone deacetylase 8 (HDAC8) and protein arginine methyltransferase 5 (PRMT5), and their role in suppressing immunotherapeutic responses in MDA-MB-231 triple-negative breast cancer (TNBC) cells. Epigenetic modifications upregulate the expression of immune checkpoint proteins, including the integrin-associated transmembrane protein cluster of differentiation 47 (CD47), which enables metastatic cancer cells to evade immune surveillance by inhibiting macrophage-mediated phagocytosis. These modifications also increase the expression of programmed death-ligand 1 (PD-L1), further promoting immune evasion by inducing T-lymphocyte apoptosis. The key objectives of this study were to determine whether (i) fast-food components (AA, MSG, NaNO2, and SS) can directly upregulate the epigenetic enzymes HDAC8 and PRMT5 in MDA-MB-231 cells without prior metabolic activation, and (ii) elevated HDAC8 and PRMT5 expression can induce the overexpression of the immune checkpoint proteins CD47 and PD-L1. Our findings reveal that prolonged exposure to MSG, AA, and SS upregulated the expression of epigenetic enzymes HDAC8 and PRMT5, upregulated oncogenic signaling, and enhanced the stemness-associated features in TNBC cells. These changes are associated with enhanced metastasis and reduced immunotherapeutic effects. Interestingly, our studies revealed that the combined presence of CD47 and HDAC8 inhibitors enhanced macrophage-mediated phagocytosis, thereby enabling immune cells to engulf cancer cells, improved the therapeutic response in TNBC, and promoted anticancer activities. These findings emphasize the importance of personalized dietary strategies for improving the efficacy of cancer immunotherapy and support the integration of specific epigenetic inhibitors with immune checkpoint inhibitors to amplify the therapeutic outcomes.