Immunotherapy and Microbiota for Targeting of Liver Tumor-Initiating Stem-like Cells

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) remains one of the more incurable diseases. Thus, finding an HCC treatment is urgent for this unmet medical need. Immunotherapy is a break-through treatment that may help 15–20% of HCC patients. In this review, pharmacological and immune-therapeutical targeting of druggable cancer drivers, immune checkpoints, and long non-coding RNAs for HCC and cholangiocarcinoma are discussed. ABSTRACT: Cancer contains tumor-initiating stem-like cells (TICs) that are resistant to therapies. Hepatocellular carcinoma (HCC) incidence has increased twice over the past few decades, while the incidence of other cancer types has trended downward globally. Therefore, an understanding of HCC development and therapy resistance mechanisms is needed for this incurable malignancy. This review article describes links between immunotherapies and microbiota in tumor-initiating stem-like cells (TICs), which have stem cell characteristics with self-renewal ability and express pluripotency transcription factors such as NANOG, SOX2, and OCT4. This review discusses (1) how immunotherapies fail and (2) how gut dysbiosis inhibits immunotherapy efficacy. Gut dysbiosis promotes resistance to immunotherapies by breaking gut immune tolerance and activating suppressor immune cells. Unfortunately, this leads to incurable recurrence/metastasis development. Personalized medicine approaches targeting these mechanisms of TIC/metastasis-initiating cells are emerging targets for HCC immunotherapy and microbiota modulation therapy.