The word “immunity” has become a buzzword of sorts in many areas, including the wellness industry, alternative healing practices, and, of course, modern medicine. However, the word “immunity” has been so overused that its meaning has become obscured. In this article, we will be talking about immunity under a strict medical definition. 

The immune system forms a barrier of defense against attacks from harmful pathogens. There are various means by which an individual can strengthen his or her immunity. Trained immunity, for example, is achieved following exposure to infectious agents or vaccines, allowing the body to mount a more rigorous defense should the same exposure occur the second time. 

“In addition to what has been seen in experimental animal models, there is now ample evidence that trained immunity is a component of the human host response to pathogens.” Divangahi and colleagues wrote in Nature Immunology. “Epidemiological studies have shown that vaccination with certain live vaccines provides heterologous protection against unrelated pathogens.”

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Of course, the body itself contains immune cells that can counter an infection and resolve it all on its own. It is only when its natural means to do so is inadequate or compromised that physicians turn to vaccines and immunotherapies to further strengthen the immune response.

Immunotherapies have a unique way of strengthening the immune system by modifying the immune system to elicit antitumor capabilities (when used in patients with cancer). Under certain circumstances, scientists have observed the ability of immunotherapies to limit or reverse the pathological phenotypic transformation typically observed in patients with cancer. 

The Vulnerability of the Liver to Injury 

The liver plays a central role in regulating important biological functions, including filtering blood from the gut before passing it on to the rest of the body. 

“The liver has a notable capacity to remove gut-derived pathogens, and their derived Pathogen-Associated Molecular Patterns (PAMP), such as lipopolysaccharide (LPS), toxins and Damage-Associated Molecular Patterns (DAMP) from the portal circulation,” Argemi and colleagues wrote in Advances in Cancer Research. 

To carry out these functions adequately and without compromise, the liver contains the highest number of resident macrophages in the body, also known as Kupffer cells. The liver also contains a rich concentration of natural killer and natural killer T cells. These immune cells allow the liver to carry out its immune regulatory function without being damaged in the process.

Read more about cholangiocarcinoma etiology 

However, like all organs in the body, diseases can knock the existing immunological equilibrium off-balance, impairing the liver’s function and transforming it into a pathological entity in its own right. Several diseases come to mind: hepatitis B and C, metabolic syndrome-associated fatty liver disease, excessive alcohol consumption, and copper accumulation in Wilson disease. 

These diseases, if left untreated, start inducing liver damage from one degree of severity to another. Continuous injury to the liver eventually results in the patient having advanced liver fibrosis. In addition, this inflammatory and fibrotic environment predisposes the patient to developing primary liver cancers, especially intrahepatic cholangiocarcinoma, and hepatocellular carcinoma. 

Generally, there are 2 principles that drive oncogenesis: the first is a somatic mutation in a driver gene; the second is when immune surveillance is inadequate or insufficient. When inflammation and cell death combine, it creates a perfect storm, resulting in intense replicative stress in hepatocytes and hepatic progenitor cells. 

Liver Immunotherapies 

Let’s briefly look at how primary liver cancers arise from an immunological point of view. A combination of antigenic modulation, immunological tolerance, and tumor-derived soluble factors allow tumor cells from a primary liver cancer to begin to acquire survival capacity against the host’s immune attack. This is the point at which “homeostasis gradually proceeds from immune surveillance to equilibrium and further immune escape during tumor progression,” Zheng and colleagues wrote in the Journal of Experimental & Clinical Cancer Research. 

It thus follows that immunological intervention should be able to limit or reverse any pathological phenotypic transformation. In other words, immunotherapies play a role in constructing an antitumor environment needed for both innate and adaptive immunity to thrive. 

It is worth mentioning that the term “immunotherapy” covers a wide range of therapeutic strategies that target the immune system. These include, for example, B lymphocytes-targeted strategies, natural killer cell-based interventions, and myeloid cell-based therapies. Each therapeutic strategy works in its own way and has its own advantages and shortcomings. 

The longstanding problem with cancer treatment is deeply rooted in immunology: how do physicians destroy cancer cells without overtly weakening the host’s immune system, putting the patient in danger of dying from simple infections? How do physicians boost immunity without upsetting the delicate immune balance in the body?

Read more about cholangiocarcinoma treatment 

“[Cytokine release syndrome], an overshooting inflammatory response triggered by iatrogenic or pathogenic causes, is the most notable adverse effect accompanied with immunotherapy,” Zheng et al wrote. “Complications such as neurotoxicity, hepatotoxicity, infection, and severe cutaneous adverse reactions have been reported in engineered T cell therapy.” 

Much research into the finetuning of existing immunotherapies for primary liver cancers is ongoing; a positive immunological equilibrium may yet be achieved against pathological processes without compromising overall immune health. 


Argemi J, Ponz-Sarvise M, Sangro B. Immunotherapies for hepatocellular carcinoma and intrahepatic cholangiocarcinoma: current and developing strategiesAdv Cancer Res. Published online March 26, 2022. doi:10.1016/bs.acr.2022.03.002

Divangahi M, Aaby P, Khader SA, et al. Trained immunity, tolerance, priming, and differentiation: distinct immunological processesNat Immunol. Published online December 8, 2020. doi:10.1038/s41590-020-00845-6

Zheng Y, Li Y, Feng J, et al. Cellular based immunotherapy for primary liver cancerJ Exp Clin Cancer Res. Published online August 9, 2021. doi:10.1186/s13046-021-02030-5