Immunotherapy has shown significant improvement in the survival of patients with hepatocellular carcinoma (HCC) compared to TKIs as first-line treatment. Unfortunately, approximately 30% of HCC exhibits intrinsic resistance to ICIs, making new therapeutic combinations urgently needed. The dysregulation of the Notch signaling pathway observed in HCC can affect immune cell response, reducing the efficacy of cancer immunotherapy. Here, we provide an overview of how Notch signaling regulates immune responses and present the therapeutic rationale for combining Notch signaling inhibition with ICIs to improve HCC treatment. Moreover, we propose using exosomes as non-invasive tools to assess Notch signaling activation in hepatic cancer cells, enabling accurate stratification of patients who can benefit from combined strategies.

Myelopoiesis provides for the formation and continued renewal of cells belonging primarily to the innate immune system. It is a highly plastic process that secures the response to external and internal stimuli to face acute and changing needs. Infections and chronic diseases including cancer can modulate it by producing several factors, impacting proliferation and differentiation programs. While the lymphocytic compartment has attracted major attention due to the role of adaptive immunity in anticancer immune response, in recent years, research has found convincing evidence that confirms the importance of innate immunity and the key function played by emergency myelopoiesis. Due to cancer’s ability to manipulate myelopoiesis to its own advantage, the purpose of this review is to outline myelopoiesis processes within the tumor microenvironment and suggest possible therapeutic lines of research to restore the physiological functioning of the host’s immune system, with a special outlook on hepatocellular carcinoma (HCC).