HCC usually occurs in the setting of advanced chronic liver disease, such as advanced hepatic fibrosis or cirrhosis, or chronic hepatitis B with necro-inflammatory activity. In these settings, a plethora of inflammatory and immune mediated responses contribute to the development and survival of HCC.

Kupffer cells, which form part of the reticuloendothelial system of the liver, are the resident macrophages found in hepatic sinusoids. Pattern recognition receptors found on these cells are stimulated by pathogen-associated molecular patterns (PAMPs) leading to the expression of pro-inflammatory cytokines such as IL-6, as well as immunomodulatory molecules including IL-10 and TGF-β [25]. Mouse studies have shown liver sinusoidal endothelial cells expressing low levels of major histocompatibility complex (MHC) class II molecules CD80 and CD86. Vital for helper T cell differentiation, the lack of these molecules provides a mechanism of immune escape for HCC [25,26].

Another mechanism of immune evasion by cancer cells is through the upregulation of T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs). CD4+CD25+ Tregs account for 5–10% of the CD4+ T cell population in the human body. These cells are known to suppress both CD4+ and CD8+ T cells through various means including secretion of TGF-β, IL-10, and IL-35 [27,28,29]. CTLA-4, expressed and activated on Tregs, has a higher affinity for CD80 and CD86 which acts as a competitive inhibitor to CD28, a T cell activator. Through this binding, CTLA-4 can activate indoleamine-2,3-dioxygenase (IDO) and subsequently suppress T cell mediated cytotoxic immune responses [30]. A meta-analysis from 2014 including twenty-three studies showed patients with HCC had 87% more circulating Tregs compared to healthy controls [29].

Similarly, MDSCs have been shown to suppress CD4+ and CD8+ T cells, inhibit natural killer cell cytotoxicity, and prompt the development of Tregs [31]. Accumulation of MDSCs in the liver leads to interaction with Kupffer cells, inducing PD-L1 expression on their surface. PD-L1 interacts with PD-1 and leads to suppression of IFN-γ [31]. MDSCs along with tumor associated macrophages (TAMs) also play an important role in angiogenesis: secretion of VEGF, platelet-derived growth factor (PDGF), and matrix metalloproteinase-9 (MMP-9) by TAMs and MDSCs leads to increased tumor vasculature, providing nutrients for tumor growth [32,33]. In turn, increased expression of PD-1 on T cells has been associated with incomplete response to HCC local-regional therapy and impaired survival, possibly mediated by the phenomenon of T cell exhaustion [34].

Through secretion by Tregs and MDSCs, anti-inflammatory cytokines promote tumor growth and are associated with a worse prognosis [35]. Some of the cytokines studied in HCC include the previously mentioned IL-10 and TGF-β. While IL-10 has been shown to be increased in patients with HCC compared to those with only cirrhosis or healthy controls, it is also elevated in those with chronic viral hepatitis [36]. Therefore, this immune-suppressive cytokine may be useful as an HCC tumor marker, though with limited utility in those with chronic viral hepatitis. Meanwhile, TGF-β, initially thought to be tumor suppressive, functions as a tumor promoter in later stages of HCC. Produced by tumor cells, macrophages, or Tregs, it downregulates the antitumor response by various mechanisms: it inhibits the activation of dendritic cells, promotes M2 polarization of TAMs, impairs the effector functions of T cells and NK cells, and promotes the generation of induced Treg cells [37]. One recent mouse study demonstrated that FGFR4 contributes to tumor proliferation and invasion through activation by TGF-β1 in the extracellular signal-related kinase (ERK) pathway; silencing FGFR4 expression was found to inhibit this activity [38]. Higher levels of TGF-β1 have been shown to be correlated with higher tumor grade, shorter survival, and overall poor prognosis [39,40]. In addition, higher TGF-β1 and TGF-β levels, respectively, have been associated with poor response to the TKI sorafenib and ICI pembrolizumab [41,42].

Several signaling pathways have also been studied in the development and progression of HCC. These include the Ras/Raf/MAPK, PI3/AKT/mTOR, JAK/STAT, and the Ubiquitin-Proteasome pathway. Transcription factors including c-myc and c-jun, among others, are associated with these pathways and are involved in 30–60% of HCCs [43]. Of these, one of the most crucial is the Wnt/β-Catenin pathway, with 20–40% of HCC cases harboring mutations within this complex [43]. Specifically, mutations in CTNNB1 which encodes β-catenin, as well as AXIN1 and APC encoding other important components, have been shown to occur in up to a combined 35% of human HCC samples [44]. Furthermore, activation of this pathway is shown to mediate resistance to ICI treatment for HCC, with upregulation of this signaling pathway correlating to lower overall survival rates and resistance to anti-PD1 therapies [45,46].