An omics-based drug-HIFU combination therapy discovery for ferroptosis treatment of TNBC.

Combination therapy, as a vital strategy in cancer treatment, aims to overcome the limitations of monotherapies by combining two or more drugs or treatments to enhance antitumor efficacy. However, the unclear interactions between different therapies and the difficulty of precisely identifying effective combination treatments remain major challenges. In this study, we developed an omics-based drug-HIFU combination therapy discovery framework taking ferroptosis treatment of triple-negative breast cancer (TNBC) as a paradigm. Using the transcriptomics of a large TNBC cohort, drug sensitivity databases, and transcriptomics of high-intensity focused ultrasound (HIFU)-treated cells, the interaction network between HIFU, key ferroptosis genes, and potential drugs was constructed to predict and identify novel drugs that target ferroptosis and synergize with HIFU. It was found that 11 candidate ferroptosis drugs demonstrated synergistic cytotoxicity with HIFU in 4T1 cells, which lacked previous reports. Especially, HIFU, by upregulating IL-6 expression by 2.69-fold, reduced the IC50 of panobinostat in 4T1 cells by 5.27-fold. Panobinostat was subsequently loaded into platelet-mimicking liposomes (Pan-PML) for tumor targeted drug delivery to amplify the synergistic effect of panobinostat and HIFU. Importantly, the combination of HIFU and Pan-PML resulted in significant inhibition of tumor growth in the 4T1 tumor model, with 50 % of mice remaining free of tumor and lung metastasis compared to those treated with HIFU or Pan-PML alone. Mechanistically, it was discovered that Pan-PML, in combination with HIFU, significantly inhibited histone deacetylase (HDAC) activity to 1/50 of the original level and further reduced the expression of the ferroptosis-related gene SIRT3 to 19.17 % of baseline, thereby synergistically promoting ferroptosis in tumor cells and activating anti-tumor immunity. Thus, this omics-based drug-HIFU combination therapy discovery framework provides an innovative method to screen the combination therapy, which leverages the synergistic effects of existing drugs and HIFU and enables combination treatments to maximize antitumor efficacy.