Modulation of Inflammation-Driven Hepatocarcinogenesis: The Hepatic Immune Microenvironment, Gut–Liver Axis, and Neuroregulation

Abstract

Hepatocellular carcinoma (HCC) is a highly malignant cancer closely related to the chronic inflammation induced by persistent liver damage. Various risk factors, including chronic hepatitis B/C virus infections, alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease, aflatoxins exposure, and metabolic disorders, contribute to genetic mutations in hepatocytes, leading to sustained cellular damage and apoptosis. These processes foster a chronic inflammatory microenvironment that activates hepatic stellate cells, promotes extracellular matrix deposition, and triggers aberrant regenerative repair, ultimately advancing liver fibrosis, cirrhosis, and HCC. The transition from chronic liver injury to HCC is governed by two interconnected mechanistic layers: initiating triggers—viral infection and hepatocyte death—that provide the substrate for malignant transformation, and modulatory systems that determine the trajectory of this process. Recent studies have revealed that diverse cell types and molecular signaling pathways form an intercellular regulatory network that fosters an inflammatory and carcinogenic microenvironment. This review focuses on three such modulatory systems—the hepatic immune microenvironment, the gut–liver axis, and neuroregulation—and examines how their interplay influences malignant behaviors including cell transformation, proliferation, and apoptosis. We systematically overview the key cellular constituents, fundamental molecular mechanisms, and core signaling pathways governing inflammation-induced hepatocarcinogenesis, and discuss potential therapeutic targets emerging from current research. A deeper understanding of these fundamental pathological mechanisms provides a conceptual framework for elucidating the initiation and progression of HCC. It also offers a theoretical basis for the future development of preventive and targeted therapeutic strategies, although the translation of these mechanistic insights into clinically effective interventions—particularly for cancer prevention—will require rigorous validation in large-scale, prospective human studies.

Introduction

Liver cancer is the third leading cause of cancer-related mortality worldwide. Hepatocellular carcinoma (HCC), which constitutes over 80% of all liver cancer cases, has a five-year survival rate of only 18%.¹ The main risk factors for HCC vary across regions—chronic hepatitis B predominating in Asian populations, chronic hepatitis C and ALD showing elevated rates in American Indian and Black populations, and MASLD increasingly prevalent across all groups.² Beyond these epidemiological patterns, emerging evidence indicates that racial and ethnic differences extend beyond etiology to fundamentally influence the molecular pathways driving the inflammation–cancer transition. First, the distinct etiological composition across populations implies that hepatocytes are subjected to qualitatively different inflammatory insults, which may activate distinct downstream signaling cascades and shape the trajectory of hepatocarcinogenesis.

Second, comparative transcriptomic analyses have revealed significant race-specific differences in the hepatic immune microenvironment. A TCGA-based study comparing Asian and Caucasian HCC patients demonstrated that Asians exhibit elevated ubiquitin ligase activity and suppressed inflammatory responses, whereas Caucasians show enhanced cytokine signaling, complement activation, and xenobiotic metabolism.³ Another study confirmed that White and Asian liver cancer patients possess fundamentally different tumor immune microenvironments, which may influence the efficacy of immunotherapy.⁴ Notably, African-American/Black HCC patients exhibit dysregulated type I interferon signaling, a pathway intimately linked to chronic inflammation, which may contribute to their increased incidence and decreased survival.⁵

Furthermore, HCC displays a marked sexual dimorphism; it is the fifth most frequent cancer and the second leading cause of cancer death in males globally. This disparity may be attributed to the protective role of estrogen signaling pathways.^6,7

Third, germline genetic variations and epigenetic modifications—such as population-specific DNA methylation patterns and miRNA expression profiles—can modulate the expression of key inflammatory mediators and alter the threshold for inflammation-driven malignant transformation.^8,9 Collectively, these findings suggest that the inflammation–cancer transition in the liver is not a uniform process but rather a racially and environmentally modulated continuum, with implications for both risk stratification and the development of population-tailored preventive strategies.

Chronic HBV infection drives persistent hepatic inflammation through sustained viral replication and host immune responses, which collectively promote the stepwise progression from hepatitis to fibrosis, cirrhosis, and eventually HCC.¹⁰ In the case of hepatitis C virus (HCV) infection, chronic hepatitis C develops after approximately six months. A subset of patients with chronic hepatitis C experience progressive liver fibrosis, with studies indicating that approximately 20% to 30% of these patients progress to cirrhosis or even liver cancer over a 20-year period. Collectively, chronic inflammation induced by hepatitis B and C is a significant contributor to the development of HCC. Inflammatory environments lead to the continuous secretion of pro-inflammatory factors that target hepatocytes and stromal cells, thereby facilitating immune evasion, inhibiting apoptosis, promoting tumor cell proliferation, and inducing immune modulation. This process can induce DNA mutations, exacerbate genomic instability, and result in mitochondrial dysfunction.^11–17

Alcohol-associated Liver Disease (ALD) constitutes a chronic liver injury primarily induced by alcohol consumption. Persistent ALD may progress to Alcohol-associated Hepatitis (AH), with severe alcoholic hepatitis patients experiencing high short-term mortality rates. Research indicates that persistent inflammation is particularly prevalent among AH patients. Alcohol consumption results in hepatocellular damage and the subsequent release of inflammatory mediators. Concurrently, the hepatic immune milieu is disrupted, leading to neutrophil infiltration and the release of neutrophil extracellular traps (NETs), which further exacerbate liver injury and may progress to cirrhosis or even hepatocellular carcinoma. Additionally, alcohol consumption can disrupt the gut microbiota homeostasis, activates the inflammasome, amplifying disease severity.^18,19

Metabolic dysfunction-associated fatty liver disease (MASLD) represents the most prevalent chronic liver condition globally. Its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), significantly elevates the risk of liver fibrosis and HCC. In MASH, excessive lipid accumulation leads to hepatocyte senescence and apoptosis, coupled with innate immune activation. This process involves the coordinated action of macrophages, neutrophils, and hepatic stellate cells, which collectively drive persistent hepatic inflammation and fibrogenesisr, ultimately progressing to HCC.^20–24

While the majority (80–90%) of HCC cases arise in the context of viral hepatitis, metabolic steatohepatitis, liver fibrosis or liver cirrhosis, it is also important to recognize that a small but significant subset of HCCs can develop in the absence of overt inflammation or cirrhosis, driven by de novo genetic alterations (eg, CTNNB1, TERT promoter, and ARID1A mutations).^25,26 Nevertheless, chronic inflammation remains the dominant pathogenic driver for most cases, firmly establishing HCC as a prototypical inflammation-associated cancer.^27,28 Multiple risk factors of HCC induce hepatocyte damage and death, followed by compensatory proliferation, leading to the accumulation of genetic mutations and disruption of chromosomal stability. Simultaneously, damage-associated molecular patterns (DAMPs) released from the damaged hepatocytes activate intrahepatic immune cells, triggering immune responses and remodeling the liver immune microenvironment. Ultimately, persistent liver injury progresses to HCC.²⁹ The transition from chronic uncontrolled inflammation to HCC development is termed the inflammation–cancer transition in the liver, a process involving diverse cell types and distinct regulatory mechanisms.

To frame the discussion that follows, it is useful to recall the conceptual architecture of cancer biology. The malignant transformation of a normal cell into a tumor cell is governed by a set of acquired functional capabilities, collectively termed the “hallmarks of cancer”, which include sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, replicative immortality, induction of angiogenesis, activation of invasion and metastasis, reprogramming of energy metabolism, and—centrally relevant to this review—tumor-promoting inflammation and avoidance of immune destruction.³⁰ Chronic inflammation contributes to each of these hallmarks through multiple mechanisms: inflammatory cells (macrophages, neutrophils, T cells) release reactive oxygen and nitrogen species that induce genomic instability and mutations; pro-inflammatory cytokines such as IL-6, TNF-α, and TGF-β sustain proliferative signaling and activate anti-apoptotic pathways; and the inflammatory milieu fosters an immunosuppressive microenvironment that enables immune evasion. Conversely, the ability of cancer cells to avoid immune destruction is not merely a passive consequence of inflammation but an active process shaped by the dynamic interplay between tumor cells and the host immune system. In the context of the liver—an organ uniquely exposed to gut-derived microbial products and endowed with an inherently tolerogenic immune environment—these two hallmarks are particularly salient. The persistent inflammatory state induced by viral infection, metabolic stress, or alcohol exposure creates a permissive soil for the acquisition of these hallmark capabilities, and the regulatory systems that modulate hepatic inflammation determine the pace and likelihood of their emergence.

Current research delineates the hepatic regulatory systems through three primary dimensions: the immune microenvironment, the gut-liver axis, and neural regulation. While the hepatic immune landscape is well-characterized and serves as the foundation for checkpoint blockade therapies,^31,32 the gut-liver axis has emerged as a critical determinant of metabolic and immunological homeostasis. Dysregulation of this axis is implicated in the progression of chronic inflammatory conditions, such as MASLD and PSC, toward hepatocarcinogenesis.^33,34 In contrast, the role of the nervous system remains relatively under-explored, despite evidence suggesting that autonomic innervation significantly influences hepatic metabolism and oncogenesis. Notably, neural regulation is not an isolated phenomenon but is integrally linked with the immune microenvironment and the gut-liver axis, suggesting that targeting hepatic neural pathways represents a promising therapeutic frontier.^35,37

In this review, we systematically dissect the inflammation–cancer transition in the liver into two interconnected mechanistic layers. The first layer comprises the initiating events—viral infection and hepatocyte death³⁸—which provide the mutational substrate and the persistent inflammatory drive that fuel hepatocarcinogenesis. The second layer comprises the modulatory systems—the hepatic immune microenvironment, the gut–liver axis, and neuroregulation—which determine the trajectory and tempo of malignant progression by shaping the inflammatory milieu that enables the acquisition of cancer hallmarks. We then discuss the therapeutic implications of targeting these regulatory networks. The purpose of this review is to provide a comprehensive framework for understanding inflammation-driven HCC by systematically dissecting its initiating triggers and modulatory systems, and to identify emerging therapeutic opportunities informed by this layered perspective.

Literature Search Strategy

This review encompasses 199 references published between 1978 and 2026, with 157 sourced from journals with an impact factor exceeding 5. Our literature search was primarily guided by keywords such as “primary liver cancer”, “chronic inflammation”, “hepatitis A virus”, “hepatitis B virus”, “neurological diseases”, “gut-liver axis”, “cell death”, and “immune microenvironment”, along with their various combinations. To ensure a comprehensive historical perspective, we diligently traced citations from pertinent high-quality reviews to incorporate foundational and seminal studies from earlier periods.

For the literature screening process, our inclusion criteria were informed by the following principles: (1) significant relevance to the issues or phenomena under discussion; (2) a strong preference for studies published in high-impact journals; and (3) a considered relaxation of impact factor thresholds for niche or highly specialized topics, provided they maintained substantial relevance. Our exclusion strategy primarily focused on eliminating redundant studies, with a preference for retaining literature that exhibits superior impact, closer thematic alignment, and broader representativeness. To prevent excessive length in the manuscript, we strictly limited our textual examples to one or two seminal studies per thematic direction.

Initiating Drivers of Hepatic Inflammation: Viral Infection as a Persistent Trigger

Chronic viral infection constitutes a prototypical initiating driver of hepatic inflammation. The following section details the molecular mechanisms through which HBV and HCV establish a persistent inflammatory state that provides both the mutational substrate and the immunological context for hepatocarcinogenesis. The initiation and progression of HCC involves multiple risk factors. In China, chronic hepatitis B (HBV) and hepatitis C (HCV) infections are the primary etiological drivers, with chronic HBV infection present in approximately 80% of HCC patients.³⁹

Studies have demonstrated that HBV promotes chronic liver inflammation and subsequent hepatocarcinogenesis through two major mechanisms.^40,41 One approach is to directly integrate the virus into the host genome, such as HBV integration at the telomerase reverse transcriptase (TERT) gene promoter region, resulting in hotspot mutations. HBV also modulates specific microRNAs and expresses viral oncoproteins that activate signaling pathways such as PI3K–AKT–STAT3, Wnt/β-catenin, and Ras–MAPK, thereby facilitating viral persistence, cell proliferation, and carcinogenesis.^42,44

During acute HBV infection, accumulated viral products sensitize hepatocytes to death ligands like tumor necrosis factor (TNF), exacerbating hepatocyte apoptosis and contributing to characteristic histopathological changes. In chronic HBV infection, liver tissue-resident memory T cells (TRM) play dual roles: CD8⁺TRM cells suppress viral replication but can also aggravate inflammation through the production of IL-2, perforin, and pro-inflammatory cytokines.^45,46 CD4⁺T cells contribute to antiviral and anti-tumor immunity by activating CD8⁺T cells and B cells via cytokine secretion. Clinical studies have identified that CD4⁺ T cell deficiency correlates with higher recurrence rates and lower survival in HCC patients.⁴⁷

Notably, HBV-related HCC patients exhibit significant infiltration of regulatory T cells (Tregs).⁴⁸ These Tregs suppress immune responses via both cell-cell contact and secretion of inhibitory cytokines including IL-10, transforming growth factor-β (TGF-β), and IL-35. Additionally, Treg expansion impairs CD8⁺T cell function, creating an immunosuppressive tumor microenvironment (TME). Therefore, modulating Treg activity has been proposed as a potential immunotherapeutic strategy for virus-associated HCC.⁴⁹ However, given the essential role of Tregs in maintaining immune homeostasis and preventing autoimmunity, systemic depletion of Tregs carries substantial risks of off-target immune-related adverse events. Future approaches will need to achieve selective modulation of tumor-infiltrating Tregs while preserving peripheral regulatory functions—a challenge that remains largely unresolved in current preclinical models.

During HCV infection, activated hepatic stellate cells (HSCs) release inflammatory cytokines and chemokines such as CXCL5 and CXCL9,⁵⁰ driving dysregulated hepatocyte proliferation and hepatic immune disorders, which promotes liver fibrosis.^51–53 Concurrently, under the stimulation of chronic HCV, the immune system continuously produces inflammatory mediators, trapping hepatocytes into a repetitive cycle of damage, death, and regeneration. This process accelerates the accumulation of gene mutations, while elevated reactive oxygen species (ROS) further compromise genomic stability,^54,55 collectively exacerbating the fibrosis-HCC progression cascade. The above mechanisms are summarized in Table 1.

Table 1.

Mechanisms Underlying Hepatitis Virus-Triggered Initiation of Hepatic Inflammation

Factor	Target/Signal/Pathway	Result	Experimental Systems
HBV	TERT gene promoter region	HBV integration at the TERT gene promoter region causes hotspot mutations.	TCGA Database and Samples from human42
	PI3K-AKT-STAT3, WNT/β-catenin, and Ras-MAPK	HBV regulates signaling pathways to promote viral invasion, cell proliferation, and carcinogenesis	Mouse model and In vitro studies43,44
	TNF	Viral product accumulation increases hepatocyte sensitivity to death ligands, resulting in hepatocyte death and histopathological changes.	Mouse model and In vitro studies (cells from human)41
	CD8+ TRM	The high expression of IL-2, perforin, and pro-inflammatory cytokines by CD8+ T cells can exacerbate liver inflammation	Mouse model and In vitro studies (cells from human)45,46
	CD4+ T cells	CD4+ T cells can activate CD8+ T cells and B cells through cytokine release, thereby enhancing intrahepatic immune responses.	Samples from Human47
HCV	CXCL5, CXCL9	Activated HSCs release inflammatory cytokines and chemokines such as CXCL5 and CXCL9, which leads to dysregulated hepatocyte proliferation and hepatic immune disorders.	Mouse model and In vitro studies (cells from human)50,53
	ROS	High ROS levels disrupt the genomic stability, collectively exacerbating the fibrosis-HCC progression cascade.	Mouse model and In vitro studies (cells from human)54,55

Thus, HBV and HCV establish a persistent inflammatory state that provides the initial fuel for hepatocarcinogenesis. However, the outcome of this chronic infection—whether it progresses to HCC or remains contained—is critically shaped by the host’s regulatory systems that modulate immune responses, microbial signals, and neural inputs. These modulatory systems, which interpret and respond to the inflammatory signals initiated by viral infection, are the focus of the following sections.

Initiating Drivers of Hepatic Inflammation: Hepatocyte Death as the Source of Danger Signals

Hepatocyte death, regardless of its etiology, constitutes the second major initiating driver of hepatic inflammation. The following section details the diverse forms of cell death and the danger signals they release, which collectively establish the inflammatory milieu that fuels hepatocarcinogenesis. Various risk factors for acute and chronic liver diseases, including viral infections, high-fat diets, and alcohol intake, can induce hepatocyte death, trigger chronic liver inflammation, and ultimately promote HCC development.⁵⁶ For example, report in The Lancet indicates that MASLD is an emerging risk factor for hepatocellular carcinoma, primarily through its progression to MASH, which drives hepatocarcinogenesis. By 2050, MASH-induced HCC cases are projected to increase by 35%. Currently, the prevalence of steatotic liver disease in China is approximately 30–40%, making it the most common chronic inflammatory liver condition.⁵⁷ Throughout the progression from inflammatory liver disease to hepatocellular carcinoma, diverse mechanisms of cell death are frequently observed. This observation suggests that targeting hepatocyte death may serve as an effective therapeutic strategy to disrupt this pathogenic cascade.

Hepatocyte Apoptosis, Necroptosis and Liver Inflammation-Cancer Transition

Apoptosis is integral to both the clearance of intracellular pathogens and the pathogenesis of a spectrum of liver diseases. This form of programmed cell death is observed in various conditions, including viral hepatitis, fatty liver disease, hepatic ischemia-reperfusion, and drug-induced liver injury.⁵⁸ Cysteinyl aspartate-specific proteinase 8 (Caspase-8) is a key regulator of this process and exhibits a dual role in the inflammation-cancer transition. On the one hand, it can promote hepatocyte apoptosis by cleaving downstream Caspase-3 in an enzyme activity-dependent manner, thereby eliminating damaged hepatocytes to prevent the accumulation of mutations and the release of inflammatory factors, thus maintaining hepatic homeostasis. On the other hand, it senses DNA damage through its non-apoptotic functions,⁵⁹ promotes H2AX (γ H2AX) phosphorylation, initiates DNA repair mechanisms, and causes hepatocyte proliferation stress, exacerbating the occurrence and development of HCC.

Consistently, clinical data from relatively small or heterogeneous patient cohorts indicate that HCC patients with low Caspase-8 expression have a higher overall survival rate. However, it is important to note that the functional understanding of this dual role — particularly the non-apoptotic, pro-tumorigenic function of Caspase-8 — is largely derived from mouse models and needs further validation in human settings.⁶⁰

In the absence of Caspase-8 activity, the cell death pathway shifts to necroptosis, a form of regulated necrosis.⁶¹ Hepatocyte necroptosis also plays a dual role in the liver inflammation–cancer transition. While it can suppress tumor progression by eliminating cells when apoptosis is impaired, it also promotes the release of damage-associated molecular patterns (DAMPs), triggering robust inflammatory responses that foster a tumor-promoting microenvironment and facilitate mutation, proliferation, and metastasis of tumor cells.^62,64 Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is regarded as the core executor of hepatocyte necroptosis, and which binds to RIPK3 to form the “necrosome” complex, activating mixed lineage kinase domain-like protein (MLKL) to induce plasma membrane rupture. RIPK1 is a double-edged sword in the inflammation-cancer transition in the liver. On the one hand, activation of RIPK1 promotes the transcription of key pro-inflammatory factors such as chemokine (CC-motif) ligand 2 (CCL2), activates HSCs, and enhances infiltration of CCR2⁺ macrophages,⁶³ thereby promoting liver inflammation, liver fibrosis, and HCC initiation. Meanwhile, studies have shown that the kinase independent function of RIPK1 also plays a role in promoting DEN induced liver tumorigenesis.⁶⁴ And the inhibition of RIPK1 expression can reduce pathological features of metabolic dysfunction-associated steatohepatitis (MASH) in mice fed a high-fat diet.⁶⁵ On the other hand, liver-specific knockout of the RIPK1 gene leads to proteasomal degradation of the tumor necrosis factor receptor-associated factor 2 (TRAF2), excessive activation of Caspase-8, and decreased NF-κB activity, thereby promoting HCC development.⁶⁶ Similarly, the absence of RIPK3 can cause excessive proliferation of liver cancer cells, accelerating liver cancer progression. However, excessive activation of RIPK3, while causing liver cancer cell death, also regulates the activity of NF-κB, leading to a large release of cytokines and exacerbation of inflammatory reactions, which in turn have a profound impact on hepatic inflammation-cancer transition.^63,67,68

Hepatocyte Necrosis and Liver Inflammation-Cancer Transition

Necrosis constitutes a pro-inflammatory mode of cell death initiated by the loss of plasma membrane integrity, typically due to a noxious stimulus, or by the disruption of the lysosomal membrane.⁶⁹ During the process of hepatocyte necrosis, intracellular components such as interleukin-33 (IL-33) and high mobility group box-1 protein (HMGB1) are released into the extracellular space, triggering intrahepatic inflammatory responses that damage adjacent hepatocytes.⁷⁰ HMGB1 signaling has been shown to promote hepatocarcinogenesis by regulating matrix metalloproteinase (MMP) activity via the IL-6/STAT3–miR-21 axis. Clinically, HMGB1 is associated with the prognosis of HCC and holds potential as a novel supplementary biomarker for HCC.^71,72 Additionally, cyclophilin D (CYPD) is involved in hepatocyte necrosis. Studies have shown that inhibiting CYPD can alleviate acetaminophen-induced drug-induced liver injury and high-fat diet-induced fatty liver injury in mice, improves the inflammatory environment of the liver, and thereby impedes the inflammation-cancer transition.^70,73–75

Hepatocyte Pyroptosis and Liver Inflammation-Cancer Transition

Pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) represent key initiators of pyroptosis.⁷⁶ Pyroptosis is a type of programmed cell death triggered by inflammasomes, primarily dependent on Caspase-1, Caspase-4/5/11, gasdermin D (GSDMD) and gasdermin E (GSDME).^77–83 During the process of hepatocyte pyroptosis, cells continuously swell until their membranes rupture, releasing IL-1β, IL-18 and heat shock proteins (HSPs), which trigger a strong inflammatory response within the liver.^83,84

Inflammasomes play a crucial role in liver cell injury, activation of liver immune cells, and the initiation and progression of liver inflammation. Several inflammasome sensor proteins, including NOD-like receptor thermal protein domain associated protein 1 (NLRP1), NLRP3, and absent in melanoma 2 (AIM2), are expressed in Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), portal vein fibroblasts, and HSCs. They can directly or indirectly promote hepatitis and liver fibrosis, inducing HCC. Studies have shown that activating inflammasomes using uric acid crystals can upregulate the expression of transforming growth factor beta 1 (TGF-β1) in HSCs.⁸⁵ Pathogen-associated molecular patterns (PAMPs) from the intestine and DAMPs from hepatocytes can activate inflammasomes in KCs, release IL-1β and IL-18, and activate HSCs.⁸⁶ In patients with alcoholic hepatitis, the expression levels of Caspase-1 and NLRP3 increase, and elevated levels of IL-1β are found in the serum of patients with severe alcoholic hepatitis.^87,88 Furthermore, it is indicated that the NLRP3 inflammasome is gradually activated during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), suggesting that the NLRP3 inflammasome is related to the transition from MASLD to metabolic dysfunction-associated steatohepatitis (MASH). Inhibition of NLRP3 can effectively suppress the progression of MASLD and cirrhosis, avoiding further deterioration of liver health.^89–91 However, the direct role of the NLRP3 inflammasome in HCC remains unknown. It can promote tumorigenesis by supporting survival, proliferation, metastasis, angiogenesis, and immune evasion,⁹² yet may also exert anti-tumor effects through direct cell death induction.⁹³

Through analysis of the TCGA database, GSDME is highly expressed in HCC patients and is significantly negatively correlated with patient survival. Upregulation of GSDME, CCL4, and CCL5 in MAFLD-related cirrhosis and HCC implicates GSDME-driven inflammation in the hepatic inflammation-cancer transition.^94,95

Hepatocyte Autophagy and Liver Inflammation-Cancer Transition

In the context of alcoholic liver disease, metabolic dysfunction-associated steatohepatitis (MASH), or drug-induced liver injury, hepatocyte organelles such as mitochondria, the production of reactive oxygen species (ROS) is increased from hepatocyte organelles such as mitochondria, the endoplasmic reticulum, and peroxisomes. Beyond causing direct organellar damage, excessive ROS also acts as a signaling molecule that activates autophagy pathways to eliminate damaged cellular components.⁹⁶ Autophagy, a lysosome-dependent degradative process essential for maintaining cellular homeostasis, plays a dual role in the hepatic inflammation–cancer transition.⁹⁷ During early stages, it protects hepatocytes by clearing exogenous microbes and endogenous debris, thereby reducing DNA damage and DAMP release, which helps maintain genomic stability and suppress inflammation. However, after the onset of HCC, autophagy can serve as a nutrient source for tumor cells.⁹⁸ Additionally, during liver injury, hepatocyte autophagy can promote the production of ROS, induce oxidative stress and cell death, and stimulate compensatory proliferation—all of which further accelerate HCC progression. The mechanisms underlying hepatocyte death‑elicited inflammation‑cancer transition are summarized in Table 2. The major hepatocyte death pathways and their dual roles in the inflammation–cancer transition are summarized schematically in Figure 1.

Table 2.

Mechanisms Underlying Hepatocyte Death-Elicited Initiation of Hepatic Inflammation

Factor	Target/Signal/Pathway	Result	Experimental Systems
Apoptosis	H2AX (γ H2AX)	Caspase-8 senses DNA damage, promotes H2AX (γ H2AX) phosphorylation, causes hepatocyte proliferation stress.	Mouse model and Samples from Human59,60
Necroptosis	MLKL	RIPK1 binds to RIPK3 to form the “necrosome” complex, activating MLKL to induce plasma membrane rupture.	Mouse model63,64
Necrosis	IL-6/STAT3-miR-21, MMP	HMGB1 signaling regulates MMP activity through the IL-6/STAT3-miR-21 pathway, inducing HCC.	Mouse model and Samples from Human71,72
Pyroptosis	IL-1β, IL-18, HSPs, Caspase-1, Caspase-4/5/11, GSDMD, GSDME	Inflammasome sensors (NLRP1, NLRP3, AIM2) activate Caspases and gasdermins, inducing HCC.	Mouse model and Samples from Human85,87,93
Autophagy	ROS	Hepatocyte autophagy promotes ROS, inducing oxidative stress in hepatocytes.	Rat model98

Figure 1.

Hepatocyte Death Pathways in Inflammation–Cancer Transition.

Targeting Hepatocyte Death to Prevent Inflammation-Cancer Transition

Targeting hepatocyte death to halt the inflammation-cancer transition represents a major focus in clinical research. Cysteine protease inhibitors like Emricasan (IDN-6556) have shown efficacy in reducing liver injury and fibrosis in murine models of chronic liver disease and in early-phase clinical trials for portal hypertension.^99,100 Cyclooxygenase-2 (COX-2) inhibitors, such as the antifungal drug ketoconazole, can cause excessive mitochondrial autophagy in liver cancer cells, promoting hepatocellular death and inhibiting tumor growth.¹⁰¹ Curcumin has been reported to trigger RIPK1/RIPK3-dependent necroptosis in activated HSCs via the JNK1/2-ROS signaling pathway in vitro, and this effect was associated with attenuated liver fibrosis in experimental models. Nevertheless, the clinical applicability of curcumin or its derivatives is constrained by poor oral bioavailability and limited liver-specific delivery. Whether such pro-necroptotic strategies can be safely harnessed to resolve fibrosis without exacerbating hepatic inflammation in humans requires further investigation.^102,103 In recent years, extensive research has also been conducted on inflammasomes. In mouse models of MASH, pharmacological inhibition of NLRP3 has been shown to ameliorate liver damage, reduce myeloid cell infiltration, and suppress liver fibrosis.^104,105 Similarly, targeting the upstream P2X7 receptor, which mediates NLRP3 inflammasome activation, has reduced inflammatory infiltration and collagen deposition in rodent injury models.¹⁰⁶ While these preclinical findings are encouraging, the translation of inflammasome-targeting strategies to human liver disease faces several hurdles, including the pleiotropic functions of inflammasomes in tissue homeostasis and host defense, as well as the lack of potent and liver-selective small-molecule inhibitors that have succeeded in late-stage clinical trials for chronic liver disease. Collectively, diverse forms of hepatocyte death serve as the ignition switch for hepatic inflammation. The DAMPs released from dying cells not only amplify local inflammation but also engage systemic regulatory circuits—including immune cells, the gut microbiota, and neural pathways—that ultimately determine whether tissue injury resolves or progresses to malignancy. In the following sections, we examine these three major regulatory systems that modulate the trajectory of the inflammation–cancer transition.

Modulatory System I: The Hepatic Immune Microenvironment in Inflammation–Cancer Transition

As introduced in the conceptual framework above, the ability of cancer cells to avoid immune destruction and to co-opt inflammation for their benefit are two hallmarks that are critically shaped by the hepatic immune microenvironment. This section details the cellular and molecular mechanisms through which this microenvironment modulates the inflammation–cancer transition. While viral infection and hepatocyte death provide the initiating inflammatory drive, it is the hepatic immune microenvironment that serves as the primary local interpreter and modulator of these danger signals. This section examines how the composition, functional state, and spatial organization of hepatic immune cells—from innate effectors to adaptive regulators—determine whether inflammation resolves or progresses toward carcinogenesis. The composition and functional orientation of the hepatic immune cell repertoire are illustrated in Figure 2, which categorizes each cell type according to its predominant pro-tumor, anti-tumor, or context-dependent role.

Figure 2.

Hepatic Immune Cell Repertoire in Inflammation–Cancer Transition.

Chronic liver injury from various etiologies, such as viral infection, alcohol exposure, and hepatic steatosis, induces hepatocyte death and the subsequent release of damage-associated molecular patterns (DAMPs). DAMP signaling not only activates immune responses but also contributes to the reprogramming of the hepatic immune microenvironment.¹⁰⁷ Under physiological conditions, the liver maintains an immune-tolerant microenvironment, where hepatic immune cells mediate inflammatory responses via cytokine and chemokine secretion to eliminate pathogens and endotoxins, thereby preserving immune homeostasis. However, during the liver inflammation-cancer transition, specific immune cell subsets are activated via distinct molecular mechanisms, leading to immune dysregulation. These alterations are significantly related to the overall prognosis and treatment sensitivity of patients. The composition and proportion ratio of immune cells in the TME of HCC play a pivotal role in cancer initiation and progression. These immune profiles are significantly correlated with clinical outcomes and responses to immunotherapy.^108–111

Natural Killer Cells and Liver Inflammation-Cancer Transition

Natural killer cells (NK cells) are critical mediators of antitumor immunity and immunomodulation, responding to exogenous infections, tissue inflammation, and carcinogenesis.^112,113 NK cells constitute 30–50% of intrahepatic lymphocytes,¹¹⁴ and they can secrete immunomodulatory factors, such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), as well as IL-1β, IL-12, IL-15, and IL-18. Clinical studies have shown that NK cell frequency in peripheral blood and tumor tissue is reduced in HCC patients, accompanied by significantly decreased IFN-γ levels; moreover, NK cell abundance positively correlates with patient survival. HCC cells can achieve immune escape through multiple mechanisms that suppress NK cell function. For instance, tumor-derived exosomal circUHRF1 has been reported to reduce NK cell infiltration and contribute to anti-PD-1 resistance, although this mechanism awaits further clinical validation.^115–117 Notably, independent of specific pathways, a substantial body of evidence has established that NK cell frequency and functional competence are consistently impaired in HCC patients, and that the extent of NK cell infiltration correlates with patient outcomes. Given the centrality of NK cells in tumor immune surveillance and their sensitivity to inflammatory cues, the status of the NK cell compartment may serve as a functionally relevant parameter of the hepatic inflammation-cancer transition.

NKT Cells, MAIT Cells, and γδ T Cells in Liver Inflammation-Cancer Transition

Innate-like T cells (ILTCs)—including natural killer T (NKT) cells, mucosa-associated invariant T (MAIT) cells, and gamma delta T (γδT) cells—exhibit MHC-unrestricted antigen recognition and possess self-renewal capacity.¹¹⁸ Intrahepatic ILTCs are regulated by multiple mechanisms and have multiple functions such as secreting pro-inflammatory cytokines, killing liver cells, and promoting tissue repair. They play a significant role in the process of hepatic inflammation-cancer transition.^119–122 NKT cells play a crucial role in eliminating external pathogens and cancer immunity. In the liver, dendritic cells (DCs), KCs, biliary epithelial cells, and other antigen-presenting cells can activate NKT cells.^123–125 The number of NKT cells all increases in several chronic liver diseases such as MASH, autoimmune hepatitis (AIH), liver fibrosis, and HCC,^126–128 suggesting pathogenic involvement. Research has shown that NKT cells promote mouse liver inflammation and activate HSC by secreting IL-4 and recruiting neutrophils. Meanwhile, by secreting IFN-α and IFN-γ, type 1 NKT cells can exacerbate Concanavalin A (ConA)-induced AIH and 2-OA-BSA induced primary biliary cholangitis (PBC).^129–132 NKT cell-mediated type 2 response characterized by secretion of IL-4 and IL-13. On the other hand, the immune regulatory function and tissue repair ability of NKT have inhibitory effects on the progression of liver diseases. For example, type 2 NKT cells can alleviate ConA and α-galactosylceramide (α-GalCer)-induced liver injury in mice by inducing a subpopulation of NKT10 (iNKT) cells and secreting IL-10.¹³³ NKT cells express C-X-C motif chemokine receptor 6 (CXCR6), which plays a role in the early stage of liver injury and inflammation by clearing damaged hepatocytes, indicating a certain anti-tumor effect of intrahepatic NKT cells in the early phase of disease.¹³⁴ In summary, different cytokines can induce phenotypic changes in NKT cells and thereby play diverse roles in hepatic inflammation-induced HCC initiation as well as HCC immunity.

MAITs are the most common T cell subsets in the human liver,¹³⁵ capable of recognizing vitamin B derivatives produced by bacteria and yeast, thereby defending against microbial invasion. Upon activation, MAITs secrete large amounts of effector molecules perforin and granzymes,¹³⁶ and pro-inflammatory cytokines such as IFN-γ, TNF-α, and IL-17.¹³⁷ Functionally, MAITs may possess certain anti-tumor effects. However, recent in vivo experimental studies have shown that MAITs promote tumor growth by suppressing T cells and NK cells activity through IL-17A.¹³⁸ Meanwhile, MAIT accumulates and produces a large amount of granzyme B in AIH and PBC patients, causing tissue damage.^139,140 In liver fibrosis, MAITs can induce a pro-fibrotic phenotype by activating HSC.¹⁴¹ Compared with wild-type C57BL/6 mice, MAIT deficient Mr1^−/− mice are immune to the effects of liver fibrosis.¹⁴² At present, there are relatively few studies on the tissue distribution, phenotype, and function of MAITs in liver diseases, and the role of MAITs in the process of inflammation-cancer transition remains to be further explored.

γδT cells are involved in various liver diseases, including MASH, AIH, liver fibrosis, and cirrhosis. Studies have shown that IL-17A secreted by γδT cells can mediate hepatocyte injury in Jα18 knockout BALB/c mice (Jα281^−/−) with AIH.¹⁴³ Knocking out γδT cells can alleviate high-fat diet-induced steatohepatitis and liver injury in mice.^144–146 In HCC, CCL4/CCL5 recruit γδT cells via CCR1/CCR5,¹⁴⁷ and subsets exert either pro- or anti-tumor effects. However, the interactions between γδT cells and tumor cells, as well as their mechanisms in TME and liver inflammation-cancer transformation, remain unclear.

Hepatic Macrophages in Liver Inflammation-Cancer Transition

Hepatic macrophages are composed of KCs and monocyte-derived macrophages (MoMFs) recruited during inflammation.¹⁴⁸ They polarize into M1 (pro-inflammatory, anti-tumor) or M2 (anti-inflammatory, pro-tumor) phenotypes in response to cytokines (eg, IL-4, IL-13, IL-10) and signaling molecules such as glucocorticoids and vitamin D3.¹⁴⁹ KCs account for ~20% of non-parenchymal liver cells.¹⁵⁰ In the early stages of liver injury, pattern recognition receptors (PRRs) on the cell membrane of KCs can recognize DAMPs released by dead hepatocytes, secreting pro-inflammatory factors such as IL-1β, IL-18, and TNF-α, etc,¹⁵¹ amplifying inflammation. In the later stages of liver injury, KCs shift toward an anti-inflammatory phenotype, secreting IL-4 and IL-10.¹⁵² Chronic KC activation is a hallmark of progressive liver disease, promoting fibrosis and HCC.^153,154

In the tumor microenvironment, macrophages are termed tumor-associated macrophages (TAMs). Their precursors are recruited via IL-4, IL-10, and CCL2.^149,155 Mature TAMs express immunosuppressive and carcinogenic factors such as apolipoprotein E (ApoE), triggering receptor expressed on myeloid cells 2 (TREM2), and inhibitor of differentiation 3 (ID3),¹⁵⁶ which help shape an immunosuppressive TME.

Dendritic Cells, T Cells, and B Cells in Liver Inflammation-Cancer Transition

Dendritic cells (DCs) are pivotal antigen, which present cells that process and present antigens to T cells via MHC-I/II pathways.¹⁵⁷ Under physiological conditions, hepatic DCs exhibit low phagocytic capacity and weak T cell stimulation, and they secrete immunosuppressive regulatory factors such as IL-10.^158,159 In liver injury or HCC, DCs can activate a large number of anti-tumor T cells.¹⁶⁰ Clinical studies indicate a significant positive correlation between intratumoral DC density and patient survival.

Besides innate immunity, adaptive immunity also critically shapes liver inflammation and tumor immunosurveillance. Studies have found that the accumulation of CD4⁺ and CD8⁺ T cells in both MASH mice and MASH patients, and CD4⁺ T cells can upregulate intrahepatic IFN-γ expression, promoting liver inflammation. However, massive death of intrahepatic CD4⁺ T cells results in impaired immune surveillance of liver tumors and facilitates HCC occurrence. Similarly, activated CD8⁺ T cells can promote liver injury induced by MASH, and after exhaustion of CD8⁺ T cells, liver cell damage in the MASH model of high-fat diet mice is alleviated.^161,162 In the TME, however, exhaustion and apoptosis of CD8⁺ T cells contribute to tumor immune escape. Conversely, Tregs, a subset of T cells characterized by expression of FOXP3, CD25, and CD4, are enriched in HCC peripheral blood and promote immune evasion and tumor progression.

B cells play a dual role: they can foster an immunosuppressive environment conducive to pre-malignant cell expansion, yet also exert anti-tumor effects by producing antibodies and activating T cells.^163–165

Neutrophils in Liver Inflammation-Cancer Transition

Tumor-associated neutrophils (TANs) exhibit a dual role of pro- and anti-tumor in HCC patients.^166–169 IFN-β, IL-1β, IL-8, and TNF-α induce TANs to polarize towards the anti-tumor N1 phenotype, while TGF-β and IL-6 drive TAN polarization towards the pro-tumor N2 phenotype. Studies have shown that TANs interact with lymphocytes within the TME and modulate their functions. N1-type TANs produce chemokines such as CCL3, CXCL9, and CXCL10, which recruit CD8⁺ T cells to the TME and secrete cytokines including IL-12 and TNF-α to activate CD8⁺ T cells, thereby exerting anti-tumor effects. In contrast, N2-type TANs express chemokines CCL2 and CCL17 to recruit macrophages and FOXP3⁺ Tregs, enhancing tumor immune escape and promoting HCC progression.¹⁷⁰

Hepatic Stellate Cells in Liver Inflammation-Cancer Transition

HSCs are primarily involved in the production of the extracellular matrix. During liver injury, HSCs are activated by DAMPs secreted from dying hepatocytes as well as paracrine signals from immune cells and LSECs. Once activated, HSCs promote the progression of liver fibrosis.^171–173

In vitro, activated HSCs (aHSCs) undergo autophagy and upregulate the expression of growth differentiation factor 15 (GDF15). Correspondingly, single-cell RNA sequencing of HCC patients revealed a significant upregulation of GDF15 expression within tumor-associated HSCs, indicating that aHSCs and GDF15 play a certain role in HCC pathogenesis. Meanwhile, aHSCs also highly express pro-inflammatory cytokines and other growth factors. In a mouse MASLD-HCC model, knockout of hepatocyte fructose-1,6-bisphosphatase 1 (FBP1) promoted HSC activation via HMGB1, leading to the release of IL-6 and CXCL1 and subsequent tumor growth.^174,175

Additionally, feedforward loop exists between HSCs and macrophages: macrophages release TNF-α and IL-1 to activate HSCs, which in turn secrete CCL2 to recruit more macrophages, collectively exacerbating liver injury.^176,177

Furthermore, chronic inflammation-driven epigenetic modifications profoundly influence HSC activation and fibrogenesis. Specifically, METTL3-mediated m⁶A methylation promotes the m⁶A-dependent translation of TGF-β1 mRNA in a cap-independent manner, thereby driving HSC activation.¹⁷⁸ Conversely, hypermethylation of promoters of key genes, such as PPARγ, RCAN1.4, and PSTPIP2, leads to their silencing, which in turn facilitates HSC activation and fibrosis progression.¹⁷⁹

The cellular mechanisms underlying hepatic inflammation-cancer transition are summarized in Table 3.

Table 3.

Cellular Mechanisms of Immune Modulation in Hepatic Inflammation–Cancer Transition

Factor	Target/Signal/Pathway	Result	Experimental Systems
NK cells	IFN-γ, TNF-α, IL-1β, IL-12, IL-15, IL-18	NK cells inhibit tumor growth through inflammatory factors	Samples from Human115,116
	circUHRF1/PD-1	Tumor cells reduce NK cells infiltration to lead resistance to anti-PD-1immunotherapy by circUHRF1	Samples from Human117
NKT cells	IL-4, IFN-α, IFN-γ	NKT cells activate HSC and recruit neutrophils to promote liver inflammation and exacerbate the disease	Mouse model128,131 and Samples from Human126,127
	IL-10,CXCR6	NKT cells alleviate liver injury through clearing damaged hepatocytes	Mouse model133
MAITs	IFN-γ, TNF-α	MAITs inhibit tumor growth through inflammatory factors	Samples from Human137
	IL-17A, granzyme B, HSC	MAITs promote tumor growth and disease like liver fibrosis by suppressing immune function and inducing inflammation microenvironment	Mouse model, In vitro studies (cell line)138,142 and Samples from Human139,141
γδT cells	CCR1/CCR5	γδT cells are recruited to the liver tumor region via interaction with CCR1/CCR5, and different γδT cell subsets have pro-tumor or anti-tumor functions	Mouse model and Samples from Human147
KC cells	TNF-α, IL-1β, IL-18	KC cells exacerbate the liver immune response in the early stages of liver injury	Mouse model151
	IL-4, IL-10	KC cells suppress inflammation in the later stages of liver injury, and long-term activation of KCs leads to HCC	Samples from Human151,152
TAMs	ApoE, ID3	TAMs play a key role in the formation of an immunosuppressive TME through anti-inflammatory and pro-cancer effects	Mouse model156
DC cells	IL-10	DCs can activate a large number of anti-tumor T cells in the context of liver injury or HCC	Mouse model and Samples from Human160
CD4+ T cells	IFN-γ	CD4+ T cells promote liver inflammation in liver injury. However, massive death of CD4+ T cells results in impaired immune surveillance of liver tumors and facilitates HCC occurrence.	Mouse model162
CD8+ T cells	CCL3, CXCL9, CXCL10, IL-12, TNF-α	CD8+ T cells have pro-tumor or anti-tumor functions in different chronic inflammatory liver diseases	Mouse model and Samples from Human161
Tregs	FOXP3, CD25, CD4	Tregs have immunosuppressive functions	Mouse model and Samples from Human161
TANs	CCL3, CXCL9, CXCL10	TANs are induced to the anti-tumor N1 phenotype to recruit CD8+ T cells	Mouse model and Samples from Human170
	CCL2, CCL17	TANs are induced to the pro-tumor N2 phenotype to recruit FOXP3+ Tregs	Mouse model and Samples from Human170
HSCs	GDF15, IL-6, CXCL1, CCL2, METTL3, PPARγ, RCAN1.4, PSTPIP2	Activated-HSCs promote the progression of liver fibrosis and HCC	Mouse model and Samples from Human174,175,178,179

Modulatory System II: The Gut–Liver Axis in Inflammation–Cancer Transition

Beyond the local immune microenvironment, the gut–liver axis provides a distal source of inflammatory modulation. This section examines how microbial-derived signals traverse the portal circulation to shape hepatic immune tone and influence the trajectory of inflammation-driven hepatocarcinogenesis. The gut microbiota has become one of the most prominent research frontiers in the field of liver cancer. Intestinal microbes play a pivotal role in maintaining the physical barrier of the intestine, supporting hepatic nutrition, facilitating immune maturation, and regulating hepatocyte proliferation.¹⁸⁰ These findings underscore the inseparable relationship between the gut-liver axis and hepatic inflammation-cancer transition. Mechanistically, gut-derived endotoxins activate hepatic macrophages via Toll-like receptor 4 (TLR4) signaling. This sustained aberrant activation represents a critical biological mechanism driving the progression from chronic liver inflammation to HCC.¹⁸¹ This process is amplified by hepatocyte-derived endogenous TLR4 ligands such as HMGB1 in early stages.¹⁸² Notably, the downstream TLR regulator like signal regulatory protein alpha (SIRPα) provides negative feedback on TLR4 signaling in both macrophages and liver parenchymal cells, modulating inflammatory cascades.¹⁸³ In rodent models, probiotic-mediated modulation of gut microbiota has been reported to improve intestinal barrier function, suppress pro-inflammatory cytokine release, and reduce hepatocarcinogenesis.¹⁸⁴ However, the inherent complexity and inter-individual heterogeneity of the gut microbiome pose substantial hurdles to the standardization of clinical interventions. For instance, a Phase II trial (NCT03785210) evaluating vancomycin in combination with ICIs for refractory HCC and liver-metastatic CRC/PDAC was prematurely terminated due to poor accrual. This setback underscores the persistent challenge of translating promising preclinical concepts into tangible clinical outcomes.

Modulatory System III: Neural Regulation in Inflammation–Cancer Transition

The nervous system provides a supra-organ regulatory layer that connects hepatic inflammation to systemic physiological states. This section examines how sympathetic and parasympathetic signals modulate liver injury, fibrosis, and the inflammatory milieu, and discusses the emerging potential of neural modulation as an intervention node. The autonomic and sensory nervous systems play critical roles in various aspects such as normal hepatic physiological functions, liver injury repair, and regeneration.^185–189 Emerging evidence indicates that the sympathetic nervous system exerts pro-inflammatory and pro-fibrotic effects by activating HSCs. Pretreatment with 6-hydroxydopamine to induce sympathetic denervation prior to CCl₄ exposure significantly attenuated hepatocyte necrosis, steatosis, and pro-inflammatory cytokine release in mice.^190,191 In spontaneously hypertensive rats, the peripheral sympathetic nerve activity is increased and they are more sensitive to CCl₄-induced hepatotoxicity. After 4 weeks of CCl₄ administration, they developed liver cirrhosis, while the control rats only exhibited mild bridging fibrosis.^192,193 Notably, while CCl₄ typically induces hepatocyte apoptosis, sympathetic denervation paradoxically increased apoptotic activity while suppressing proliferation. It is suggested that sympathetic signaling may inhibit apoptosis, potentially leading to the accumulation of damaged cells that perpetuate inflammatory responses and fibrosis.¹⁹⁴

Conversely, the parasympathetic nervous system mediates hepatoprotective and anti-inflammatory effects through macrophage-expressed α7 nicotinic acetylcholine receptors (α7nAChRs). In mice with inhibited Fas-mediated apoptosis, vagotomy markedly increased mortality, whereas co-administration of an α7nAChR agonist reduced mortality and attenuated hepatic inflammation.¹⁹⁵ Similarly, in acetaminophen-induced liver injury models, the acetylcholinesterase inhibitor can increase the survival rate and reduce hepatocyte damage, apoptosis, and inflammation.¹⁹⁶ Thus, while sympathetic activation generally exacerbates injury, vagus nerve signaling is protective across multiple hepatotoxic models. Consequently, targeted modulation of neural pathways represents a potential therapeutic strategy to impede the inflammation–carcinoma transition. Investigating the role of the nervous system in modulating this transition is particularly pertinent in contemporary contexts, where chronic stress and anxiety are prevalent and can lead to central nervous system dysfunction. It is crucial to mitigate the negative impacts of neuroendocrine pathways on hepatic health.¹⁹⁷

The roles of the gut‑liver axis and the nervous system in the hepatic inflammation‑cancer transition are summarized in Table 4. The gut-liver axis and its integration with neural regulation are depicted in Figure 3.

Table 4.

Role of Gut–Liver Axis and Nervous System in Modulating Hepatic Inflammation–Cancer Transition

Factor	Target/Signal/Pathway	Result	Experimental Systems
Gut-derived endotoxins	TLR4, HMGB1	TLR4 is persistently aberrantly activated to drive the progression from chronic liver inflammation to HCC, and HMGB1 amplifies inflammatory responses in early stages	Mouse model and Rat model181,182
Sympathetic nervous system	HSC, apoptotic	Sympathetic nervous system exerts pro-inflammatory and pro-fibrotic effects by activating HSCs and inhibiting apoptosis	Mouse model and Rat model190,192,194
Parasympathetic nervous system	α7nAChRs	Parasympathetic nervous system mediates hepatoprotective and anti-inflammatory effects through α7nAChRs	Mouse model195,196

Figure 3.

Gut–Liver Axis and Neural Regulation in Inflammation–Cancer Transition.

Future Challenges and Perspectives

Limitations of the Review

Before outlining future directions, it is important to acknowledge several limitations inherent to this review. First, while we have systematically dissected the inflammation–cancer transition into initiating triggers and modulatory systems, this conceptual framework, though heuristic, may oversimplify the intricate and non-linear interplay among these layers. Second, our discussion is primarily centered on three regulatory axes—the hepatic immune microenvironment, the gut–liver axis, and neuroregulation—and does not exhaustively cover other emerging modulators such as epigenetic remodeling, metabolic reprogramming, or the tumor stroma beyond hepatic stellate cells, which have been extensively reviewed elsewhere. Third, considering that the existing evidence is primarily derived from preclinical models, the translational potential and applicability of the elucidated mechanisms in human clinical contexts require thorough validation in future research endeavors. Finally, the discussion on neuroregulation, though a rapidly evolving frontier, remains relatively preliminary compared with the more established fields of hepatic immunology and microbiome research, reflecting the current maturity of the literature. These limitations notwithstanding, we believe our integrative framework provides a useful roadmap for understanding and targeting the inflammation–cancer transition in HCC.

Future Perspectives

The overall framework of the inflammation–cancer transition, encompassing initiating triggers, modulatory systems, and HCC outcomes, is illustrated in Figure 4. Despite substantial progress in elucidating the cellular and molecular mechanisms underlying inflammation-driven hepatocarcinogenesis, several critical challenges remain unresolved and merit future investigation.

Figure 4.

Regulatory Network of Liver Inflammation–Cancer Transition.

First, the temporal dynamics and context-dependency of the three regulatory systems are poorly understood. Most current studies capture only static snapshots of immune composition, microbial ecology, or neural activity, yet the inflammation–cancer transition is inherently a dynamic process that unfolds over years or decades. Longitudinal studies integrating multi-omics profiling at multiple time points are urgently needed to decipher the sequence of events that tip the balance from chronic hepatitis toward malignancy, and to identify the earliest actionable intervention windows.

Second, the cross-talk among the three modulatory systems remains largely unexplored at the mechanistic level. The hepatic immune microenvironment, gut–liver axis, and neural regulation are often studied in isolation, yet emerging evidence suggests that they constitute an integrated network: immune cells shape microbial ecology, microbial metabolites influence neural activity, and neural signals modulate immune effector functions.^36,198 Deciphering the hierarchical organization of this tripartite network—which nodes are primary drivers versus secondary responders, and how they compensate for each other when one component fails—represents a major frontier. Systems biology approaches combining high-dimensional single-cell profiling, metabolomics, and neural imaging with computational modeling may offer a path forward.

Third, the translational gap between preclinical discoveries and clinical applications remains wide. Most mechanistic insights are derived from genetically homogeneous mouse models that poorly recapitulate the etiological and genetic heterogeneity of human HCC. The limited availability of human liver tissues at different disease stages, the lack of robust non-invasive biomarkers for tracking inflammation–cancer transition, and the difficulties in targeting specific cell types or pathways without compromising physiological functions collectively impede progress. The development of humanized mouse models, organoid systems, and patient-derived xenografts that better reflect human disease biology, alongside the identification of circulating biomarkers for early detection and risk stratification, should be prioritized.

Fourth, the therapeutic implications of targeting the regulatory networks require careful consideration of safety and timing. While pharmacological modulation of immune checkpoints, gut microbiota, or neural pathways holds promise, the dual roles of inflammation—both tumor-promoting and tumor-suppressing, depending on context—necessitate precision approaches that avoid unintended consequences. Future clinical trial designs should incorporate biomarker-driven patient selection, adaptive dosing, and combination strategies that target multiple nodes of the regulatory network simultaneously, rather than focusing on single pathways in isolation.

Finally, emerging technologies such as spatial transcriptomics, single-cell multi-omics, and artificial intelligence-based predictive modeling are poised to transform our understanding of the inflammation–cancer transition. These tools will enable the mapping of cellular interactions within their native tissue architecture, the identification of rare but functionally critical cell states, and the prediction of individual disease trajectories. Integrating these approaches with longitudinal clinical cohorts will be essential for translating mechanistic knowledge into precision medicine strategies for HCC prevention and therapy.¹⁹⁹

Conclusions

Hepatocellular carcinoma exemplifies inflammation-driven malignancy, yet its progression from chronic liver injury to cancer is not a simple linear cascade. Rather, it emerges from the interplay between initiating drivers—viral infection and hepatocyte death—that supply the inflammatory fuel for malignant transformation, and modulatory systems that determine whether this fuel ignites into cancer or dissipates through tissue repair. In this review, we have dissected three such modulatory axes—the hepatic immune microenvironment, the gut–liver axis, and neuroregulation—that collectively govern the trajectory of the inflammation–cancer transition.

The hepatic immune microenvironment serves as the primary local interpreter of injury signals. The dynamic interplay among innate and adaptive immune cells—including NK cells, NKT cells, MAIT cells, γδT cells, macrophages, dendritic cells, T cells, B cells, neutrophils, and hepatic stellate cells—each assuming context-dependent pro- or anti-tumorigenic phenotypes, determines whether the immune response eliminates transformed cells or tolerates their outgrowth. Disruption of this balance, characterized by NK cell exhaustion, Treg expansion, and M2-polarized tumor-associated macrophages, constitutes a hallmark of HCC-permissive immune remodeling. The composition and functional state of this immune repertoire not only reflect the stage of disease but also hold prognostic and predictive value for immunotherapy response.

The gut–liver axis provides a distal source of inflammatory modulation that originates beyond the liver parenchyma. Microbial-derived endotoxins and metabolites traverse the portal circulation to activate hepatic TLR4 signaling, perpetuating a cycle of immune activation and fibrogenesis. This gut-derived input not only amplifies local inflammation but also shapes the composition and functional state of the hepatic immune repertoire. Emerging evidence suggests that manipulating the gut microbiota—through probiotics, antibiotics, or dietary interventions—may offer a tractable node for therapeutic intervention, although inter-individual variability and the complexity of microbial ecology pose substantial challenges for clinical translation.

The nervous system adds a supra-organ regulatory layer that connects hepatic inflammation to systemic physiological states. Sympathetic signaling generally accelerates inflammation and fibrosis by activating hepatic stellate cells and inhibiting hepatocyte apoptosis, while parasympathetic (vagal) signaling exerts hepatoprotective effects through α7 nicotinic acetylcholine receptors on macrophages. This emerging dimension highlights the possibility of neural modulation as a novel intervention strategy, particularly given the prevalence of chronic stress and autonomic dysfunction in modern populations. However, the mechanistic details of neuro-immune crosstalk in the liver remain incompletely understood and warrant further investigation.

Critically, these three systems do not operate in isolation. Immune cells shape microbial ecology; microbial metabolites influence neural activity; neural signals modulate immune effector functions. This tripartite network constitutes an integrated regulatory hub that couples local liver injury with systemic homeostasis. Deciphering the temporal dynamics and contextual determinants of these interactions represents a key frontier for future research.

While the mechanistic rationale for targeting these regulatory networks is compelling, its translation into clinical practice—particularly for cancer prevention—requires rigorous validation in biomarker-driven, long-term human trials. Pending such evidence, current clinical recommendations should remain grounded in established measures, including antiviral therapy, lifestyle modification, and surveillance for at-risk populations. Addressing these challenges will require not only technological advances but also interdisciplinary collaboration among hepatologists, immunologists, microbiologists, neurobiologists, and computational biologists. By embracing this integrative vision, the field can move beyond the current reductionist paradigm toward a systems-level understanding of how immune, microbial, and neural inputs converge to shape the fate of the inflamed liver—ultimately informing the design of mechanism-based, patient-tailored strategies to intercept HCC before it develops.

Funding Statement

This work was supported by grants from the Shanghai Key Laboratory of Cell Engineering (14DZ2272300).

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

All authors declared that there are no conflicts of interest.