The incidence of hepatobiliary cancer has increased worldwide in recent years. These tumor entities translate into high recurrence and mortality rates, poor prognosis and clinical outcome. The management of hepatobiliary cancer is challenging and demands in most cases referral to a specialized high volume center where meticulous therapeutic interventions and advanced surgery can be performed. Unfortunately, only limited therapeutic modalities are available and curative surgery or LTX are often precluded due to the advanced disease at time of diagnosis. In this palliative setting, chemotherapy, radiation or best supportive care remain the only pillars of medical care. There is an urgent unmet need for adjunct therapeutic modalities for hepatobiliary cancer. Hereby, the role of the host immune system, after falling into desuetude in the past, has been nowadays increasingly recognized as a powerful tool in the armamentarium of available options. Overwhelming data demonstrates the formidable ability of various entities of the innate and adaptive immune system not only to be efficiently applied as vectors of anticancer treatment, but also help refine the diagnostic strategies. The latter translates into improved risk stratification and enhanced ability to identify subgroups of patients with negative tumor profiles and poor prognosis. Taken together, these insights can help enhance the efficacy of cancer management and deliver more individualized approaches in an era of personalized medicine. In the current studies, we were able to demonstrate the prognostic significance of various aspects of the host immune system and establish links that presume functional networks. This enabled us to outline them as an autonomous immunologic construct in the setting of human cancer. The main conclusions were that tumor-infiltrating monocytes/macrophages subtypes, related angiogenesis vectors and the formation of histologic necrosis in the tumor microenvironment are strongly associated. This coherent immunologic construct exerted a significant influence on patients’ overall and recurrence-free survival and qualified as an independent marker of predictiveness. The presented studies generated data that could help efficiently categorize patients in subgroups of increased risk for unfavorable clinical outcome. Furthermore, these results may represent a novel molecular pathway for immunologic checkpoint inhibition in human hepatobiliary cancer. Future studies are needed to better explore and define the implied mechanistic links, which will not only facilitate a better understanding of the tumor biology, but also optimize the management of cancer.