MicroRNAs at the Crossroad between Immunoediting and Oncogenic Drivers in Hepatocellular Carcinoma

SIMPLE SUMMARY: In recent years, treatments enhancing the antitumor immune response have revealed a new promising approach for advanced hepatocellular carcinoma (HCC). Beside favorable results in about one third of patients, much still remains to be done to face primary nonresponse, early, and late disease reactivation. Understanding the mechanisms underneath immune system modulation by immune checkpoint inhibitors in HCC might give additional opportunities for patient selection and combined approaches. MicroRNAs have emerged as relevant modulators of cancer cell hallmarks, including aberrant proliferation, invasion and migration capabilities, epithelial-to-mesenchymal transition, and glycolytic metabolism. At the same time, they contribute to the immune system development, response, and programs activation, with particular regard towards regulatory functions. Thus, miRNAs are relevant not only in cancer cells’ biology, but also in the immune response and interplay between cancer, microenvironment, and immune system. ABSTRACT: Treatments aimed to reverse the tumor-induced immune tolerance represent a promising approach for advanced hepatocellular carcinoma (HCC). Notwithstanding, primary nonresponse, early, and late disease reactivation still represent major clinical challenges. Here, we focused on microRNAs (miRNAs) acting both as modulators of cancer cell hallmarks and immune system response. We outlined the bidirectional function that some oncogenic miRNAs play in the differentiation and program activation of the immune system development and, at the same time, in the progression of HCC. Indeed, the multifaceted spectrum of miRNA targets allows the modulation of both immune-associated factors and oncogenic or tumor suppressor drivers at the same time. Understanding the molecular changes contributing to disease onset, progression, and resistance to treatments might help to identify possible novel biomarkers for selecting patient subgroups, and to design combined tailored treatments to potentiate antitumor approaches. Preliminary findings seem to argue in favor of a bidirectional function of some miRNAs, which enact an effective modulation of molecular pathways driving oncogenic and immune-skipping phenotypes associated with cancer aggressiveness. The identification of these miRNAs and the characterization of their ‘dual’ role might help to unravel novel biomarkers identifying those patients more likely to respond to immune checkpoint inhibitors and to identify possible therapeutic targets with both antitumor and immunomodulatory functions. In the present review, we will focus on the restricted panel of miRNAs playing a bidirectional role in HCC, influencing oncogenic and immune-related pathways at once. Even though this field is still poorly investigated in HCC, it might represent a source of candidate molecules acting as both biomarkers and therapeutic targets in the setting of immune-based treatments.