ANNOUNCEMENTS
Triple Negative Breast Cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks estrogen, progesterone, and HER2 receptors, rendering it unresponsive to most targeted therapies. Conventional chemotherapy remains the primary treatment modality, yet recurrence rates and resistance are alarmingly high. This study explores a novel combinatorial therapeutic approach involving activation of the innate immune cGAS–STING pathway using a STING agonist (c-di-GMP), in conjunction with gamma radiation, to induce cytotoxicity and immunogenic cell death in TNBC cells.
Four treatment conditions: untreated control, agonist only, radiation only, and combination agonist plus radiation were applied to human TNBC cell lines, MDA-MB-453 and MDA-MB-468. Significant micronuclei production was found by chromosomal examination in the radiation-treated and combinatorial groups, suggesting increased DNA damage. A significant decrease in viable cells was shown by cell viability assays, especially in the combination treatment group, indicating a synergistic cytotoxic impact.
Canonical activation of the cGAS–STING pathway was confirmed by quantitative PCR analysis of immune-related gene expression, which revealed a significant elevation of IL6 and IFNβ in the combinatorial group. It's interesting to note that TREX1 and cGAS were both increased at the same time, suggesting either an excess of cytosolic DNA load or possible feedback mechanisms. However, there were no discernible transcriptional alterations in the STING gene, indicating that the agonist largely works via post-translationally activating preexisting protein pools.
These findings highlight the potential of STING agonists to enhance the immunogenic effects of gamma radiation in TNBC. The observed activation of immune signaling and increased DNA damage support the rationale for further preclinical evaluation. This combinatorial strategy could serve as a promising alternative to conventional treatments and pave the way for immune-based therapeutic interventions in TNBC.
Keywords: Triple Negative Breast cancer, breast cancer, agonist, radiation, combinatorial.
