Ubiquitination in hepatocellular carcinoma immunity

Abstract

Hepatocellular carcinoma (HCC) is the sixth most prevalent malignancy worldwide, and represents a major global health challenge. While surgical resection at early stages offers favorable prognosis with 5-year survival rates exceeding 70%, the clinical reality in China reveals a contrasting scenario, where over 60% of patients present with advanced disease, resulting in a dramatic decline in 5-year survival to below 12.5%. The immunological landscape plays a pivotal role in HCC pathogenesis and progression, comprising two complementary arms: the innate immune system's rapid-response mechanism for immediate tumor surveillance and the adaptive immune system's antigen-specific targeting with immunological memory capabilities. Emerging evidence has highlighted ubiquitination, a sophisticated post-translational modification system, as a critical regulator of immune homeostasis in HCC pathogenesis. This molecular process exerts precise control through three primary mechanisms: (1) Modulation of immune cell activation thresholds via proteasomal degradation of signaling proteins, (2) Orchestrating immune cell differentiation through stability regulation of transcriptional factors, and (3) Maintenance of immune tolerance by dynamic modification of checkpoint regulators. Such multifaceted regulation affects both innate immune recognition pathways (e.g., NF-κB and STING signaling) and adaptive immune effectors (particularly T cell receptor signaling cascades). This comprehensive review establishes a threefold Objective: First, to elucidate the mechanistic interplay between ubiquitination networks and HCC-related immune dysregulation; Second, to systematically analyze how innate immune-associated ubiquitination events drive hepatocarcinogenesis through chronic inflammation modulation; and third, to critically evaluate recent clinical advances combining ubiquitination-targeted therapies (e.g., proteasome inhibitors and E3 ligase modulators) with immunotherapeutic regimens. Our synthesis revealed that strategic manipulation of ubiquitination pathways can potentiate PD-1/PD-L1 blockade efficacy while mitigating therapeutic resistance, particularly through modulation of tumor-associated macrophages and exhausted T cell populations. By integrating fundamental mechanistic insights with translational clinical data, this review provides a conceptual framework for the development of next-generation diagnostic biomarkers and rational therapeutic combinations. The proposed strategy of ubiquitination-immune axis modulation holds significant potential to transform current HCC management paradigms, offering new avenues for precision immunotherapy for this challenging malignancy.

Keywords: Adaptive immune; E3; HBV; HCC; Innate immune; Ubiquitination.

Fig. 1

PI3K/Akt and Ras/MAPK signaling pathway processes and associated ubiquitination. Phosphorylated RTK can activate upstream proteins of the PI3K/Akt pathway and Ras/MAPK pathway, resulting in downstream Ras/Raf/MAPK cascade reaction and activation of the key protein Akt, ultimately leading to abnormal cell behavior and the occurrence of HCC. In this process, many transducers can be activated or degraded by different E3 ubiquitin ligase ubiquitination, accelerating the disorder and abnormal activation of the pathway

Fig. 2

Wnt/β-catenin signaling pathway processes and associated ubiquitination. Under normal conditions (Wnt Off), β-catenin binds to the degradation complex and is phosphorylated, subsequently recognized by E3 ubiquitin ligase (β-TrCP) and undergo ubiquitination and degragdation. The Wnt/β-catenin signaling pathway is initiated by binding of Wnt ligand protein to transmembrane protein FZD receptor (Wnt On), Dvl protein will be recruited to the cell membrane to bind FZD, and then Dvl protein interacts with Axin to recruit a protein complex composed of Axin, GSK-3β and APC. This progress allows the β-catenin protein to enter the cell and direct downstream gene transcription. Most E3 ubiquitin ligases protect against Wnt signaling pathway transduction and eventual oncogene transcription through ubiquitining and degrading related proteins, but are underexpressed in HCC

Fig. 3

NF-κB signaling pathway processes and associated ubiquitination. The NF-κB signaling pathway is classified into canonical and non-canonical pathways. The classical pathway relies primarily on the activation of the IκB kinase complex β (IKKβ) and the phosphorylation and degradation of IκB by the inflammatory immune response, leading to nuclear transcription of NF-κB (primarily p50/RelA dimer) molecules. The non-classical pathway is stimulated by a cytokine (CD40L, BAFF), which leads to the activation of NIK and IKKα, then partial degrading p100 to p52 and forming NF-κB molecules with RelB. A large number of E3 ubiquitin ligases are involved in this pathway, some acting as transducers and others activating or inhibiting the NF-κB signaling pathway by ubiquitinating and degrading related proteins

Fig. 4

HBV virus structure and related immune ubiquitination process involving HBx protein. HBx protein in HBV is involved in ubiquitination of endoplasmic reticulum related proteins and Wnt pathway related proteins, leading to immune disorders, abnormal cell proliferation, apoptosis and other physiological function resulting in HCC

Fig. 5

Diverse E3 ligases participate in the modulation of multiple signaling pathways via the ubiquitination process, playing crucial roles in either immunological activation or immune evasion through specific mechanisms. For instance, MARCHF3 - PARP1 - dsDNA complex activates the cGAS - STING pathway in dendritic cells, which is essential for initiating innate immune responses. NBR1 - associated activation of STING impacts Th cells, thereby influencing the balance of the adaptive immune response. TRIM32 recruits TBK1, leading to the induction of IFN, which is a key cytokine in antiviral and antitumor immunity. TAB 182 - CNOT4 interaction affects CD8 + T cells, potentially altering their cytotoxic function and tumor - killing ability. Moreover, SPOP - PD - L1/PD − 1 axis causes T - cell exhaustion, a major mechanism of tumor immune evasion. Evidently, numerous T - cell immune regulation processes are intricately associated with PD - L1. Consequently, targeted immunotherapy in combination with anti - PD - L1 treatment has emerged as a promising approach in the clinical management of HCC, offering new prospects for improving patient outcomes