Hyperglycaemia is a common metabolic alteration associated with breast cancer risk and progression. We have previously reported that BRCA1 restrains metabolic activity and proliferative response to IGF-I anabolic actions in breast cancer cells cultured in high glucose. Here, we evaluated the impact of normal physiological glucose on these tumour suppressive roles of BRCA1. Human breast cancer cells cultured in normal physiological and high glucose were treated with IGF-I (0–500 ng/mL). Cellular responses were evaluated using immunoblotting, co-immunoprecipitation, and cell viability assay. As we previously reported, IGF-I induced ACCA dephosphorylation by reducing the association between BRCA1 and phosphorylated ACCA in high glucose, and upregulated FASN abundance downstream of ACCA. However, these effects were not observed in normal glucose. Normal physiological glucose conditions completely blocked IGF-I-induced ACCA dephosphorylation and FASN upregulation. Co-immunoprecipitation studies showed that normal physiological glucose blocked ACCA dephosphorylation by increasing the association between BRCA1 and phosphorylated ACCA. Compared to high glucose, the proliferative response of breast cancer cells to IGF-I was reduced in normal glucose, whereas no difference was observed in normal mammary epithelial cells. Considering these results collectively, we conclude that normal physiological glucose promotes the novel function of BRCA1 as a metabolic restraint of IGF-I actions. These data suggest that maintaining normal glucose levels may improve BRCA1 function in breast cancer and slow down cancer progression.

Chimeric antigen receptor (CAR)-cell-based therapies have demonstrated remarkable clinical success in hematologic malignancies; however, their application in solid tumors remains limited, largely due to the scarcity of suitable surface antigens. TCR-like CARs offer a promising strategy to overcome this barrier by targeting peptide-HLA complexes derived from intracellular tumor-associated antigens. In this study, we investigated NK cells expressing a TCR-like CAR directed against the MAGE-A4 peptide presented by HLA-A*02:01 on tumor cells. The CAR construct incorporated CD3ζ and GITR intracellular signaling domains and was assessed in both NK-92 cells and primary peripheral blood NK cells. Our results demonstrated that MAGE-A4 CAR expression enhanced the metabolic fitness of NK-92 cells, as evidenced by increased glycolysis, basal respiration, and ATP production. Functionally, CAR-engineered NK cells exhibited significantly enhanced cytotoxicity against MAGE-A4⁺ tumor cell lines (A375, U2OS, and U266), but not against MAGE-A4⁻ targets (HCT116), confirming antigen specificity. Enhanced tumor cell killing was associated with increased CD107a degranulation, elevated granzyme B and perforin expression, and augmented TNF-α and IFN-γ production. In vivo, MAGE-A4 CAR NK-92 cells demonstrated potent antitumor activity in an A375 xenograft model. Consistent with these findings, primary NK cells expressing the MAGE-A4 CAR also displayed enhanced antitumor activity and cytokine secretion in vitro. Collectively, these findings demonstrate that TCR-like targeting of the intracellular tumor antigen MAGE-A4 using CAR-engineered NK cells enhances metabolic fitness, effector function, and antitumor activity, highlighting the potential of this approach as a promising immunotherapeutic strategy for MAGE-A4⁺ solid tumors.