MicroRNAs with Multiple Targets of Immune Checkpoints, as a Potential Sensitizer for Immune Checkpoint Inhibitors in Breast Cancer Treatment

Abstract

Breast cancer is the most common cancer type and the leading cause of cancer-associated mortality in women worldwide. In recent years, immune checkpoint inhibitors (ICIs) have made significant progress in the treatment of breast cancer, yet there are still a considerable number of patients who are unable to gain lasting and ideal clinical benefits by immunotherapy alone, which leads to the development of a combination regimen as a novel research hotspot. Furthermore, one miRNA can target several checkpoint molecules, mimicking the therapeutic effect of a combined immune checkpoint blockade (ICB), which means that the miRNA therapy has been considered to increase the efficiency of ICIs. In this review, we summarized potential miRNA therapeutics candidates which can affect multiple targets of immune checkpoints in breast cancer with more therapeutic potential, and the obstacles to applying miRNA therapeutically through the analyses of the resources available from a drug target perspective. We also included the content of “too many targets for miRNA effect” (TMTME), combined with applying TargetScan database, to discuss adverse events. This review aims to ignite enthusiasm to explore the application of miRNAs with multiple targets of immune checkpoint molecules, in combination with ICIs for treating breast cancer.

Mapping the function of MicroRNAs as a critical regulator of tumor-immune cell communication in breast cancer and potential treatment strategies

“…Preclinical evidence suggests synergistic interactions between immune checkpoint blockade and miRNAs, particularly miR-424 and miR-138, which target PD-L1, CD80, PD-1, and CTLA-4, presenting capacity for treating malignancy. Overcoming the complex interplay between miRNAs and immune checkpoints is essential to exploit the potential of miRNA-ICI synergy in breast cancer treatment ( Zhou et al, 2023a ).…”

“…As a result, it enhances the immune response against tumors, increases cytokine production, and decreases T cell apoptosis in breast cancer cells ( Zhang M. et al, 2020 ). Moreover, MiR-5119 has the ability to function as a possible controller of PD-L1 in the immunological tolerance of tissue transplants ( Zhou et al, 2023b ). In summary, miR-5119 has the ability to selectively bind to certain regions in the 3′UTRs of PD-L1 and IDO2 genes, resulting in the inhibition of protein production for both genes.…”

Synergistic Immunoregulation: harnessing CircRNAs and PiRNAs to Amplify PD-1/PD-L1 Inhibition Therapy

“…TMTME is also considered a key factor contributing to the adverse effects of miRNA therapeutics. 117,153 However, using circRNAs and piwi-RNAs (piRNAs) in cancer treatment offers a promising alternative to miRNAs with potentially greater specificity.…”

“…113 Similarly, circ-VIM not only inhibited the killing capacity of CD8+ T cells but also facilitated cell viability, clone formation, and migratory and invasive abilities of endometrial cancer (EC) cells through the activation of the Ras/ERK signaling pathway. 112 Besides, some other immune checkpoints, 117 such as PD-L2, CTLA4, B7H6, TIGIT may also be regulated by circRNA, which needs to be explored by further research. [118][119][120] Selected piRNAs Candidates…”