Data availability The data that support the plots within this paper and other findings of this study are available from the corresponding author upon request. The bulk and single-cell RNA-seq data are available as part of the Gene Expression Omnibus (GEO) SuperSeries GSE134691. Author contributions S.C. and A.G. designed the study, performed experiments, interpreted results and wrote the manuscript. J.Á.N.-Á. designed the study and experiments and interpreted data.

MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression by suppressing mRNA translation and reducing mRNA stability. A miRNA can potentially bind many mRNAs, thereby affecting the expression of oncogenes and tumor suppressor genes as well as the activity of whole pathways. The promise of miRNA therapeutics in cancer is to harness this evolutionarily conserved mechanism for the coordinated regulation of gene expression, and thus restoring a normal cell phenotype. However, the promiscuous binding of miRNAs can provoke unwanted off-target effects, which are usually caused by high-dose single-miRNA treatments. Thus, it is desirable to develop miRNA therapeutics with increased specificity and efficacy. To achieve that, we propose the concept of miRNA cooperativity in order to exert synergistic repression on target genes, thus lowering the required total amount of miRNAs. We first review miRNA therapies in clinical application. Next, we summarize the knowledge on the molecular mechanism and biological function of miRNA cooperativity and discuss its application in cancer therapies. We then propose and discuss a systems biology approach to investigate miRNA cooperativity for the clinical setting. Altogether, we point out the potential of miRNA cooperativity to reduce off-target effects and to complement conventional, targeted, or immune-based therapies for cancer.

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