Gut Microbiota Modulates Radiotherapy-Based Antitumor Immune Responses against Hepatocellular Carcinoma through STING Signaling

Abstract

<h3>Purpose/Objective(s)</h3> Studies on gut-liver communication axis have assisted in understanding both the pathophysiology of various liver diseases and mechanisms of the therapy effectiveness regulation. Radiotherapy is an important therapeutic option for unresectable HCC. However, the significance of the microbiome in regulation of responses to radiotherapy has not been well established <h3>Materials/Methods</h3> To characterize the gut microbiome related to RT sensitivity, we collected the fecal samples from a prospective longitudinal trial in 24 HCC patients receiving RT for 16s sequencing. In the mechanism study, we used FMT, flow cytometry and transcriptome sequencing to explore the effect of dysbiosis on radiotherapy. Moreover, the role of STING in radiotherapy-based antitumor immune response mediated by gut microbiota was examined in the STING-knockout (Tmem173^−/−) and cGAS-knockout (Mb21d1^−/−) mice models. <h3>Results</h3> Based on clinical and preclinical evidence, we established that the primary resistance to radiotherapy can be attributed by the disruption of gut microbiome. Mechanically, gut microbiome dysbiosis impaired antitumor immune responses by suppressing antigen presentation and inhibiting effector T cell functions in a STING-dependent manner. It is worth noting that c-di-AMP, an emerging second messenger of bacteria, might act as a bacterial STING-agonist to participate in the regulation of radiotherapy efficacy, and might be a new target for the prediction and sensitization of radiotherapy in HCC patients. <h3>Conclusion</h3> Our study identified the mechanisms by which the microbiota affects radiosensitivity, and highlighted the therapeutic potential of modulating gut microbiome in HCC patients receiving radiotherapy.