Diet-Induced Epigenetic Modifications Modulate Immunotherapy in Metastatic Breast Cancer

Mukherjee, Asmita (2026) Diet-Induced Epigenetic Modifications Modulate Immunotherapy in Metastatic Breast Cancer. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Asmita Mukherjee (19RS048)) 19RS048.pdf - Submitted Version Restricted to Repository staff only Download (18MB)

Abstract

Diet and metabolism critically influence cancer progression by modifying epigenetic regulation and antitumor immunity, yet these factors are rarely integrated into therapeutic design for cancer treatment, like triple negative breast cancer (TNBC). TNBC is more prevalent in India than in the Western countries and shows poorer survival rates. Nowadays, the importance of cost-effective sustainable ancient idea “Food is Medicine” is getting recognized. Epigenetic enzymes such as Histone Deacetylase 8 (HDAC8) and Protein Arginine Methyltransferase 5 (PRMT5) contribute to TNBC progression by repressing tumor suppressor proteins, promoting oncogenic pathways, and sustaining cancer stem cell population. Simultaneously, immune evasion mechanisms are exacerbated by environmental and dietary stressors, further impairing the effectiveness of immunotherapy. This thesis investigates how dietary components, both harmful fast-food additives and beneficial bioactive metabolites, reshape the epigenetic-immune landscape of TNBC for better treatment outcome. Chronic exposure to commonly consumed fast-food components, including monosodium glutamate (common flavour enhancer used extensively in Chinese foods, instant noodles etc), acrylamide (naturally formed components found in smoked meat, chips, cigarette smoke etc), sodium nitrite (preservative used in fish or meat curing), and sodium sorbate (preservative used in mayonnaises, cheese) were found to induce oxidative stress-driven epigenetic reprogramming, marked by upregulation of HDAC8 and PRMT5. These alterations promoted epithelial-mesenchymal transition, metastatic traits, and increased immune-evasive signaling through CD47 and PD-L1, collectively impairing macrophage- and T-cell mediated antitumor responses and limiting immunotherapy efficacy. To counteract these effects, we developed a cost-effective peptide-based combination therapy integrating an immune checkpoint inhibitor with an epigenetic small-molecule inhibitor. In contrast to harmful fast-food components, diet-derived bioactive metabolites with chemo-preventive properties showed therapeutic benefit. Sulforaphane (SFN), found in broccoli, and calcitriol, the active form of vitamin D3, effectively suppressed oncogenic epigenetic alterations and immune checkpoint expression, restoring a less aggressive tumor phenotype. Importantly, metabolic conditions played a key role in our study where diabetes mimicking high glucose conditions strengthened epigenetic activation and immune suppression. Conversely, dietary interventions were more effective under low-glucose conditions. Overall, this study establishes a direct link between diet, epigenetic regulation, and immune responses in TNBC, highlighting the opposing roles of detrimental and beneficial dietary components and supporting the development of diet-tailored therapeutic strategies for improved outcomes in aggressive breast cancer.

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