Mechanism-guided fine-tuned microbiome potentiates anti-tumor immunity in HCC

Abstract

Microbiome, including bacteria, fungi, and viruses, plays a crucial role in shaping distal and proximal anti-tumor immunity. Mounting evidence showed that commensal microbiome critically modulates immunophenotyping of hepatocellular carcinoma (HCC), a leading cause of cancer-related death. However, their role in anti-tumor surveillance of HCC is still poorly understood. Herein, we spotlighted growing interests in how the microbiome influences the progression and immunotherapeutic responses of HCC via changing local tumor microenvironment (TME) upon translocating to the sites of HCC through different "cell-type niches". Moreover, we summarized not only the associations but also the deep insight into the mechanisms of how the extrinsic microbiomes interplay with hosts to shape immune surveillance and regulate TME and immunotherapeutic responses. Collectively, we provided a rationale for a mechanism-guided fine-tuned microbiome to be neoadjuvant immunotherapy in the near future.

Keywords: HCC TME; bacteria; cell-type niche; fungi; immunotherapy; microbe-host interplay; microbiome; viruses.

Figure 1

Deep mechanistic insights of microbes’ roles in different tumor types. (A) Mechanisms by which bacteria promote carcinogenesis. (B) Mechanisms by which fungi promote carcinogenesis. (C) Oncolytic viruses and ERVs contribute to cancers immunotherapy.

Figure 2

The core sets of bacterial components play key roles in HCC carcinogenesis. Bacterial cell wall components (LPS, MDP, LTA), bacterial-related metabolin, and bacterial-induced cytokines translocated to the liver through the portal vein regulate the liver cancer immune microenvironment by interacting with liver cells, tumor cells, and immune cells, thereby promote HCC tumorigenesis.

Figure 3

The proposed state-of-art assays to identify the phenotypic core set of microbiomes (bacteria, fungi, viruses) as robust biomarkers for HCC early diagnosis and treatment. The start of the precision immunotherapy starts from sampling, which includes saliva samples, blood samples, stool samples, and biopsy tissue samples. Then Microbiome profiling includes the high-throughput sequencing and the mass spectrometry to detect metabolism and proteomics. Further analysis will classify the microbe as beneficial, harmful and bystander microorganisms to indicating their association with the responder and non-responder patients. Moreover, the causality of beneficial and harmful microbe is further characterized in anti-tumor immunity in response to ICB. Based on the association and causal evidence, the optimized neoadjuvant strategies of ICB will be administrated to responders and non-responders. The precision immunotherapy cycle help to repeat the optimization in the cycling way from patients sampling to patient treatment. It continues to motivate and enlarge our deep understanding the microbe-host interplay, which ultimately optimizing the translational research of HCC immunotherapy.