Recent progress in the immunotherapy of hepatocellular carcinoma: Non-coding RNA-based immunotherapy may improve the outcome

Hepatocellular carcinoma (HCC) is the second most lethal cancer and a leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) significantly improved the prognosis of HCC; however, the therapeutic response remains unsatisfactory in a substantial proportion of patients or needs to be further improved in responders. Herein, other methods of immunotherapy, including vaccine-based immunotherapy, adoptive cell therapy, cytokine delivery, kynurenine pathway inhibition, and gene delivery, have been adopted in clinical trials. Although the results were not encouraging enough to expedite their marketing. A major pro-portion of human genome is transcribed into non-coding RNAs (ncRNAs). Preclinical studies have extensively investigated the roles of ncRNAs in different aspects of HCC biology. HCC cells reprogram the expression pattern of numerous ncRNAs to decrease the immunogenicity of HCC, exhaust the cytotoxic and anti-cancer function of CD8 + T cells, natural killer (NK) cells, dendritic cells (DCs), and M1 macrophages, and promote the immu-nosuppressive function of T Reg cells, M2 macrophages, and myeloid-derived suppressor cells (MDSCs). Mech-anistically, cancer cells recruit ncRNAs to interact with immune cells, thereby regulating the expression of immune checkpoints, functional receptors of immune cells, cytotoxic enzymes, and inflammatory and anti-inflammatory cytokines. Interestingly, prediction models based on the tissue expression or even serum levels of ncRNAs could predict response to immunotherapy in HCC. Moreover, ncRNAs markedly potentiated the ef-ficacy of ICIs in murine models of HCC. This review article first discusses recent advances in the immunotherapy of HCC, then dissects the involvement and potential application of ncRNAs in the immunotherapy of HCC.