Oncohepatology: Navigating liver injury in the era of modern cancer therapy

Abstract

In recent years, the rapid evolution of cancer therapies has markedly increased patient survival rates. However, the incidence of adverse events caused by anticancer treatments remains high, leading to significant clinical challenges. As the central hub of drug metabolism and detoxification, the liver is susceptible to therapeutic insults. The specific mechanisms of liver injury caused by different types of antineoplastic treatments vary. Chemotherapy induces hepatic damage via oxidative stress and mitochondrial dysfunction, whereas targeted therapy disrupts signaling pathways in hepatic cells. Immunotherapy triggers immune-mediated hepatitis through cytokine storms and immune cell infiltration, and radiation therapy causes hepatic microvascular injury. Additionally, patients with preexisting chronic liver diseases (such as cirrhosis, hepatitis B/C, or nonalcoholic fatty liver disease) are more likely to face increased risks of hepatic injury during cancer treatment. Therefore, early detection and timely treatment are crucial for these high-risk populations. This review introduces the emerging field of “oncohepatology”, which illuminates the mechanisms underlying hepatic injury due to cancer treatments, summarizes the influence and management of preexisting liver disease during cancer treatment, analyzes diagnostic and therapeutic strategies for cancer treatment-associated liver function damage, and discusses potential future research directions to provide valuable insights for liver injury management in clinical oncology.

Key Words: Oncohepatology; Liver injury; Cancer therapeutic; Biomarker; Hepatoprotective strategy; Toxicity; Cancer management; Liver disease; Adverse events

Core Tip: Oncohepatology has emerged as a vital subspecialty bridging oncology and hepatology to address liver injury associated with modern cancer therapies. This manuscript unveils mechanisms of hepatic damage caused by chemotherapy, targeted therapy, immunotherapy, and radiation. It further highlights elevated risks of adverse events during cancer treatment in patients with preexisting liver diseases, thereby underscoring the necessity for tailored clinical management. Integrating diagnostic biomarkers and hepatoprotective strategies, this work also proposes a comprehensive roadmap for early detection and management of cancer treatment-induced hepatotoxicity.

INTRODUCTION

Remarkable progress in cancer therapeutics has been observed in recent decades, with the continuous emergence of new therapeutic strategies such as targeted therapies and immunotherapies, both of which have greatly increased the survival rates of cancer patients. However, as the survival time of cancer patients increases and the demand for quality of life grows, the side effects of anticancer treatment on normal organs, particularly the liver, are becoming growing clinical concerns[1]. As the body’s principal metabolic organ, the liver orchestrates crucial physiological processes including drug metabolism, detoxification, bile synthesis, lipid homeostasis, and immunological responses. Cancer drugs are metabolized mainly by the liver, increasing the risk of injury[2].

Different types of cancer treatment regimens cause varying levels of liver damage, depending on their pharmacological mechanisms. For example, chemotherapy frequently precipitates acute hepatic injury through pronounced inflammatory cascades and oxidative stress mechanisms, manifesting as hepatocellular necrosis, inflammatory infiltration, and cellular vacuolization[3]. Targeted therapies, such as tyrosine kinase inhibitors (TKIs), can also disrupt the metabolic pathways of the liver, potentially leading to liver dysfunction[4]. Moreover, immunotherapies, particularly immune checkpoint inhibitors (ICIs), may trigger excessive immune activation, resulting in immune-mediated hepatitis and associated complications[5,6]. Novel immunotherapies, such as chimeric antigen receptor T (CAR-T) cell therapy, can also lead to liver injury through CAR-T cell-associated cytokine release syndrome (CRS)[7]. Finally, radiation therapy causes DNA damage and associated hepatic microvascular injury, which may restrict treatment use or eventually lead to liver fibrosis[8].

Notably, cancer patients with preexisting liver diseases, particularly those with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, advanced cirrhosis, or nonalcoholic fatty liver disease (NAFLD), are more likely to experience hepatotoxicity during anticancer treatment[9]. Early diagnosis and timely treatment are crucial for these high-risk populations. Biomarkers play crucial roles in the early detection, risk assessment, and monitoring of cancer treatment-induced liver injury. Additionally, current hepatoprotective strategies primarily involve drug-based prevention via agents such as ursodeoxycholic acid (UDCA) and N-acetylcysteine (NAC), along with dose adjustments based on the hepatic function of cancer patients[10,11]. Related studies indicate that hepatoprotective drugs enable patients to continue treatment, reducing the need for dose reduction or treatment delays, thereby ensuring the effectiveness of antitumor therapy[12]. Furthermore, multidisciplinary teams (MDT), comprising oncologists, hepatologists, pharmacologists, pathologists, nutritionists, etc., can provide comprehensive management of liver injury in cancer patients, thereby achieving better therapeutic outcomes[13]. This review delineates the emerging discipline of “oncohepatology”, which elucidates the pathophysiological mechanisms underlying cancer treatment-induced hepatic injury, characterizes the clinical impact and management of preexisting liver comorbidities in oncology practice, systematically evaluates diagnostic and therapeutic approaches for oncotherapy-associated hepatotoxicity, and proposes future research priorities to advance precision-oriented strategies for hepatic protection in clinical oncology (Figure 1).

Figure 1 Introduction of oncohepatology. NAFLD: Nonalcoholic fatty liver disease; MDT: Multidisciplinary teams.

CANCER THERAPY-RELATED LIVER INJURIES

Liver damage resulting from cancer treatment not only reduces treatment tolerance but also increases the risk of hepatic failure. The extent of liver damage caused by different anticancer treatments varies depending on their mechanisms of action. In the following sections, the clinical manifestations and pathophysiological mechanisms of treatment-induced liver injury and its clinical management are introduced (Table 1).

Table 1 Clinical-pathological modes of liver injury caused by common anticancer treatments.

Treatment type	Examples of common drugs	Clinical-pathological modes of liver injury
Chemotherapy
Platinum-based drugs	Cisplatin, oxaliplatin	HSOS, steatohepatitis, HBV reactivation, nodular regenerative hyperplasia
Metabolism antagonists	Methotrexate, 5-fluorouracil	Steatohepatitis, cholestasis, liver cirrhosis, HBV reactivation
Alkylating agent	Cyclophosphamide, busulfan	Hepatocellular injury, cholestasis, HSOS, HBV reactivation
Alkaloids (derivatives)	Paclitaxel, irinotecan	Steatohepatitis, HSOS, hypersensitivity reaction, HBV reactivation
Antitumor antibiotics	Doxorubicin, mitomycin	HSOS, hepatocellular injury, hypersensitivity reaction
Targeted therapy
BCR-ABL kinase inhibitor	Imatinib, nilotinib	Cholestasis, hepatocellular injury, HBV reactivation
VEGFR kinase inhibitor	Sunitinib, sorafenib	Hepatocellular injury, HSOS
EGFR kinase inhibitor	Gefitinib, afatinib	Cholestasis, hepatocellular injury, autoimmune hepatitis
Immunotherapy
PD-1/PD-L1 inhibitors	Pembrolizumab, durvalumab	Autoimmune hepatitis, bile duct injury or cholangitis, HBV reactivation
CTLA-4 inhibitors	Ipilimumab	Autoimmune hepatitis, bile duct injury or cholangitis, HSOS, HBV reactivation
CAR-T cell therapy		CRS, HBV reactivation
Radiotherapy		Hepatocellular injury, HSOS, Budd-Chiari syndrome

HSOS: Hepatic sinusoidal obstruction syndrome; HBV: Hepatitis B virus; BRC-ABL: Breakpoint cluster region-Abelson; VEGFR: Vascular endothelial growth factor receptor; EGFR: Epidermal growth factor receptor; PD-1/PD-L1: Programmed cell death protein/ligand 1; CTLA-4: Cytotoxic T lymphocyte-associated antigen-4; CAR-T: Chimeric antigen receptor T; CRS: Cytokine release syndrome.

Chemotherapy-related liver injuries

While chemotherapeutic interventions remain fundamental in malignancy management, demonstrating relatively high efficacy in tumor suppression and survival enhancement, their hepatotoxic potential of these agents considerable clinical challenges[14]. Drug-induced liver injury caused by chemotherapeutic agents significantly impacts therapeutic efficacy and may lead to irreversible liver function damage in severe cases. Moreover, chemotherapy can exacerbate preexisting hepatic conditions, particularly HBV, leading to progressive deterioration of liver function. Studies have shown that the pathogenesis of chemotherapy-induced hepatotoxicity primarily involves three primary mechanisms: Reactive metabolite generation through phase I oxidative processes, immunological injury, and mitochondrial dysfunction[15].

The clinical manifestations of liver function damage caused by different types of chemotherapy drugs vary. Methotrexate, a folate metabolism antagonist, inhibits RNA and DNA synthesis in the liver, causing cell cycle arrest that directly harms hepatocytes. Long-term low-dose treatment of methotrexate may induce or worsen fatty liver disease, and liver fibrosis[16]. Similarly, 5-fluorouracil, another metabolic antagonist, can cause direct toxicity and accumulation of metabolic products, leading to hepatic steatosis and even acute liver failure[17].

Platinum-based drugs are another commonly used type of chemotherapy in clinical practice. Oxaliplatin, which is commonly used in the treatment of advanced colorectal, ovarian, and other cancers, can induce liver toxicity primarily by causing hepatic sinusoidal obstruction syndrome (HSOS). This syndrome results from endothelial cell damage in the hepatic sinusoids, leading to impaired hepatic blood flow, and may progress to liver failure under severe conditions[17,18]. Cisplatin, induces liver toxicity primarily through oxidative stress, leading to hepatocyte damage characterized by elevated levels of liver enzymes, fatty liver, and, in severe cases, acute liver failure. Studies have shown that cisplatin-related hepatic steatosis and liver toxicity are associated with increased oxidative stress and immune responses within hepatocytes[19]. Additionally, doxorubicin is associated with long-term liver dysfunction and fibrosis. It directly induces hepatocyte death by inhibiting topoisomerase II and interfering with DNA replication; however, it may also cause liver damage mediated through elevated oxidative stress, enhanced apoptotic activity, and increased necrotic cell death[20]. Overall, these toxic effects not only hinder treatment outcomes but can also lead to treatment interruption or dose reduction, negatively impacting the long-term efficacy of cancer therapy.

Targeted therapy-related liver toxicity

Targeted therapies function through the inhibition of specific molecular signaling pathways within tumor cells, thereby suppressing neoplastic growth and enhancing treatment specificity. Despite their selective targeting mechanisms, these therapeutic agents can induce hepatotoxicity[21]. TKIs, exemplified by imatinib and sunitinib, represent the predominant targeted therapeutic options in the management of various malignancies including chronic myeloid leukemia and renal cell carcinoma. The hepatotoxic manifestations of TKIs are predominantly characterized by elevated levels of transaminases[22]. Imatinib, a selective breakpoint cluster region-Abelson kinase inhibitor, has widespread application in chronic myeloid leukemia treatment. Some studies have suggested that imatinib can cause autoimmune hepatitis, HBV reactivation, and toxic hepatitis[23,24]. The mechanism may involve inhibition of breakpoint cluster region-Abelson kinase activity by imatinib, thereby disrupting the mitochondrial electron transport chain and causing overproduction of reactive oxygen species[23,24].

Another example is sunitinib, a vascular endothelial growth factor receptor kinase inhibitor, which has been associated with a spectrum of hepatic complications from transient elevations in enzymatic levels to rare instances of severe hepatic failure. Both hepatocellular injury patterns and cholestatic manifestations have been documented, particularly in patients with underlying liver pathology. The underlying pathophysiological mechanisms include mitochondrial dysfunction, reactive oxygen species generation, leading to cell apoptosis[25]. TKIs may increase the risk of hepatitis in patients with preexisting hepatic impairment. Therefore, adjusting the therapeutic dosages of targeted agents is crucial for treating hepatically impaired patients to reduce severe hepatotoxicity. For severe hepatic dysfunction (Child-Pugh C), the significantly increased toxicity risk requires a thorough risk-benefit assessment before drug administration. Systematic monitoring of hepatic function parameters, including aminotransferase and bilirubin levels, is essential for enabling timely therapeutic modifications[26].

Immunotherapy-related liver toxicity

ICIs, including programmed cell death protein/ligand 1 (PD-1/PD-L1) inhibitors (e.g., pembrolizumab and nivolumab) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) inhibitors (e.g., ipilimumab), have revolutionized the treatment of various cancers, including melanoma, non-small cell lung cancer, etc. By blocking checkpoint molecules such as PD-1/PD-L1 and CTLA-4 to increase antitumor immunity and relieve T-cell suppression, they also disrupt immune tolerance, causing immune-related adverse events (irAEs). Immune-mediated hepatitis arises from autoreactive T-cell activation targeting hepatocytes or biliary epithelia, manifesting as elevated levels of liver enzymes (alanine transaminase/aspartate transaminase) and histopathological features resembling autoimmune hepatitis[27,28]. Notably, compared with PD-1/PD-L1 inhibitors, CTLA-4 inhibitors are associated with a significantly greater incidence of immune-related hepatitis[29,30]. Emerging evidence underscores an elevated risk of severe irAEs with treatment based on PD-1/PD-L1 inhibitors paired with CTLA-4 inhibitors due to synergistic immune activation[5].

Patients with preexisting chronic liver diseases, such as NAFLD or viral hepatitis, are more susceptible to ICI-related hepatotoxicity. Therefore, for patients with chronic liver diseases, close monitoring of liver function is recommended during PD-1 inhibitor therapy[31]. Severe immune-mediated hepatic injury can progress to hepatic failure. In such cases, corticosteroid therapy, primarily using methylprednisolone, constitutes the first-line therapeutic intervention for suppressing excessive immune responses[27]. Clinical evidence has indicated favorable responses to corticosteroid therapy in the majority of patients with immune-mediated hepatitis[32]. Grade 4 hepatic injury necessitates increased corticosteroid dosages, and up to 30% of these patients may develop resistance to initial treatment, warranting second-line immunosuppression. Prompt therapeutic intervention is crucial for preventing progression to hepatic failure, with a clinical response typically observed within 1-2 months[33].

The development of CAR-T cell therapies targeting novel tumor-associated antigens has emerged as a transformative approach in oncology. However, this therapeutic modality is complicated by off-tumor/on-target toxicity, a phenomenon wherein antigen expression on healthy tissues leads to unintended damage, posing a major obstacle to the clinical translation of these therapies. A hallmark complication of CAR-T cell activation is CRS, which is characterized by rapid systemic elevation of inflammatory mediators that culminate in fever, chills, hemodynamic instability (tachycardia, hypotension), and respiratory compromise (hypoxia, dyspnea). Notably, emerging evidence implicates CRS-associated hepatotoxicity as a critical concern, ranging from transient transaminitis to fulminant acute liver failure, as a critical concern[34,35]. The mechanistic pathways through which CAR-T cells mediate liver injury are still under fully investigation, particularly the complex interactions between cytokines such as interleukin-6 and pyroptosis pathways, which contribute to systemic inflammation and hepatotoxicity[36,37]. Current management algorithms prioritize early intervention with tocilizumab, an interleukin-6 receptor antagonist, for CRS mitigation, whereas glucocorticoids serve as rescue therapy for refractory cases[7,38]. Nevertheless, specific hepatotoxicity incidence rates still remain unclear, and significant knowledge gaps persist regarding risk stratification biomarkers and organ-specific mitigation strategies. Targeted investigations are imperative for optimizing the safety profile of next-generation CAR-T cell constructs.

Radiation-induced liver injury

Radiation therapy, particularly when used in the treatment of abdominal and thoracic malignancies, frequently induces liver injury. This pathological condition manifests through multiple mechanisms, including hepatocellular deterioration, cholestatic dysfunction, and potential progression to hepatic failure. The pathophysiological basis of radiation-induced liver injury (RILI) primarily stems from radiation-mediated oxidative stress, microvascular deterioration, etc. Recent studies have emphasized that radiation-induced DNA damage and oxidative stress are crucial factors that trigger hepatocellular injury and hepatotoxicity[39]. The resulting cellular disturbance and inflammatory cascade trigger immune responses, which subsequently compromise microvascular integrity and promote liver fibrosis. These adverse effects significantly impact therapeutic outcomes in cancer patients[40].

Radiation therapy can also lead to HSOS, which typically present with characteristic features including hepatomegaly, ascites, and jaundice. HSOS originates from endothelial cell damage in the hepatic sinusoids, culminating in hepatic congestion and associated symptoms. The underlying mechanisms include radiation-induced oxidative stress and microvascular damage, thereby impairing liver function and blood flow[41,42]. Prompt recognition remains crucial, as unmanaged cases may progress to irreversible hepatic failure. In radiation therapy planning for liver-related cancers, controlling the radiation dose and minimizing the volume of the liver exposed to radiation are key strategies to reduce the incidence of RILI. Techniques such as stereotactic body radiotherapy and proton therapy have demonstrated relative improvements in sparing the liver and precisely targeting tumors while protecting surrounding healthy liver tissue. These methods minimize adverse reactions such as hepatomegaly, ascites, and jaundice[43].

Advanced radiation techniques such as intensity-modulated radiation therapy (IMRT) demonstrate superior efficacy in minimizing hepatic radiation exposure, thereby substantially reducing the risk of RILI. Compared with traditional 3D conformal radiotherapy, IMRT better targets tumors while minimizing healthy liver tissue exposure. Studies comparing IMRT with other techniques have shown that IMRT provides superior liver protection, particularly by reducing healthy liver tissue exposure, thereby lowering the incidence of hepatotoxicity[44]. Additionally, knowledge-based planning strategies have been developed to optimize IMRT, thereby reducing liver damage while maintaining tumor control and reducing the risk of liver injury[45,46].

TUMOR AND PREEXISTING LIVER DISEASES

Cancer patients often have primary liver diseases like cirrhosis, HBV, HCV, and NAFLD. These conditions heighten the risks of cancer treatment. Preexisting liver diseases can significantly influence drug metabolism, possibly reducing treatment efficacy and impacting the overall prognosis. Consequently, it is of paramount importance to thoroughly comprehend the specific considerations and management strategies when treating cancer patients with concomitant liver conditions.

Cirrhosis and cancer therapy

Patients with cirrhosis face distinct challenges when undergoing cancer treatment, as liver dysfunction impairs the liver’s capacity to metabolize anti-cancer drugs. This diminished metabolic capacity can lead to drug accumulation, increasing the risk of toxicity and liver-related adverse effects[9]. In the context of chemotherapy administration, cirrhotic patients demonstrate heightened susceptibility to severe hepatotoxicity and myelosuppression. This vulnerability is particularly pronounced with agents such as methotrexate, oxaliplatin, and doxorubicin. Chemotherapy dose modifications based on hepatic function parameters are essential for minimizing hepatic burden and preventing drug accumulation[15]. For patients classified as Child-Pugh A, standard chemotherapy doses may be used with close liver function monitoring. However, for those with Child-Pugh B and C cirrhosis, whose ability to metabolize drugs is significantly impaired, the risk of liver-related complications is considerably higher, and the prognosis worsens as multi-organ dysfunction develops[47].

Radiotherapy administration in cirrhotic patients warrants particular consideration due to the elevated risk of hepatic decompensation and RILI. The therapeutic application of radiation necessitates judicious implementation, particularly in advanced hepatic disease. Clinicians must carefully weigh the benefits of radiation against the risk of exacerbating liver damage and may opt for alternative treatment modalities or more conservative approaches[48]. The administration of targeted therapies presents additional complexities in cirrhotic patients. TKIs, including sunitinib and sorafenib, may precipitate hepatic dysfunction, necessitating dose modifications proportional to the degree of hepatic impairment[26].

Immunotherapeutic approaches introduce distinct challenges in the cirrhotic population due to heightened susceptibility to immune-mediated hepatic injury. ICIs, encompassing anti-PD-1/PD-L1 and anti-CTLA-4 agents, potentiate immune responses that may precipitate immune-mediated hepatic damage. This risk is particularly pronounced in cirrhotic patients, where hepatic dysfunction correlates with increased severity of irAEs. Research demonstrates that immune-mediated hepatic injury in cirrhosis, particularly in decompensated cases, may progress to chronic hepatic failure. Vigilant monitoring coupled with appropriate corticosteroid or alternative immunosuppressive therapy is imperative[49,50]. Therefore, cancer treatment in cirrhotic patients requires individualized treatment plans, close liver function monitoring, and multidisciplinary collaboration.

HBV and HCV infections and cancer therapy

Chronic HBV and HCV infections are major risk factors for hepatocellular carcinoma (HCC) and other cancers, posing significant challenges in cancer management. The predominant concern during cancer treatment of HBV-infected patients centers on viral reactivation risk. Immunosuppression induced by chemotherapy may potentially trigger dormant HBV reactivation, subsequently precipitating severe hepatic injury or failure[51-53]. Anticancer therapy, such as rituximab, significantly increase the risk of HBV reactivation[54,55]. Clinical protocols mandate HBV DNA quantification prior to cancer therapy initiation in HBV-infected patients, followed by prophylactic antiviral administration (specifically entecavir or tenofovir) to prevent reactivation. Upon HBV reactivation detection, prompt modifications to both antiviral regimens and cancer therapeutic protocols become imperative[53,56].

While HCV reactivation during cancer therapy is less frequent than HBV, careful monitoring remains necessary. The advent of direct-acting antivirals has revolutionized the treatment of HCV, significantly reducing the incidence of liver cirrhosis and HCC. For HCV-infected patients undergoing chemotherapy or other treatments, combining direct-acting antivirals with cancer therapy is a key strategy to mitigate liver-related adverse events and improve patient outcomes[57,58].

NAFLD and cancer therapy

NAFLD, currently the most prevalent chronic hepatic disorder globally, exhibits strong associations with obesity, type 2 diabetes mellitus, and elevated risks of HCC[59]. The characteristic hepatic steatosis and chronic inflammatory state in NAFLD predispose patients to increased hepatotoxicity during cancer treatment. Both chemotherapeutic agents and targeted therapies potentially aggravate hepatic injury in NAFLD patients. Studies have shown that NAFLD is associated with an increased prevalence of metabolic syndrome, including insulin resistance and hypertension, which may further complicate cancer treatment by affecting both tolerance and efficacy[60].

Cancer treatment in NAFLD patients requires individualized care, with careful monitoring of liver function during therapy. Therapeutic modifications, including chemotherapy dose adjustments, may be warranted. In addition, lifestyle interventions such as dietary modifications and regular physical activity have been shown to reduce liver enzyme levels, alleviate liver stress, and improve overall treatment outcomes[61]. These measures are particularly important in NAFLD patients, as they can help mitigate liver-related side effects and enhance the effectiveness of cancer therapy.

BIOMARKERS IN ONCOHEPATOLOGY

In the field of oncohepatology, biomarkers serve essential functions, as knowledge of their levels helps clinicians detect hepatic injury early, anticipate treatment-associated hepatotoxicity, and evaluate therapeutic outcomes. The systematic incorporation of these biological indicators into clinical protocols improves patient care management and optimizes hepatoprotective interventions, thereby minimizing treatment-related adverse effects. In this part, critical biomarkers utilized for diagnostic assessment, prognostic evaluation, and therapeutic response monitoring in cancer treatment-induced hepatic injury will be examined.

Diagnostic biomarkers

The prompt identification of hepatic injury remains paramount for ensuring patient safety and optimizing oncological interventions. For conventional monitoring, primarily serum transaminases (aspartate transaminase and alanine transaminase) and bilirubin measurements are relied upon to assess hepatocellular damage and biliary dysfunction. Although these parameters reflect general hepatic functional status, their limited specificity precludes accurate differentiation among various forms of liver injury[62]. Recent research has identified several emerging biomarkers with greater potential for early diagnosis. For example, galectin-3 are being explored as biomarkers for liver fibrosis and inflammation, and by measuring their levels, liver pathology can be detected at earlier stages[63]. Furthermore, extracellular vesicles and their molecular cargo, comprising microRNAs and specific proteins, have demonstrated significant potential as early diagnostic indicators of hepatic injury. Research has shown that hepatocyte damage induces increased extracellular vesicle release, with specific microRNA signatures detectable during initial disease stages, indicating superior diagnostic sensitivity[64,65]. In the context of cholangiocellular function assessment and cholestatic injury diagnosis, particularly in the context of chemotherapy and targeted therapy-induced hepatotoxicity, gamma-glutamyl transferase and alkaline phosphatase remain standard biomarkers. However, these markers are limited in terms of sensitivity and specificity, especially for distinguishing between types of liver damage or predicting early injury. Therefore, additional emerging biomarkers are needed to increase diagnostic accuracy[66].

Prognostic biomarkers

In personalized cancer therapy, prognostic biomarkers serve as crucial indicators for assessing liver injury risk and optimizing therapeutic interventions. While conventional hepatic function assessment tools, including the Child-Pugh and model for end-stage liver disease scoring system, remain widely implemented in hepatic disease management, these traditional metrics demonstrate inherent limitations when applied to cancer therapy scenarios, where hepatotoxicity manifestations exhibit complex, multifactorial characteristics that necessitate more refined biomarker systems[67]. Recent studies have explored novel biomarkers such as the albumin-bilirubin grade, to increase prognostic accuracy. For example, albumin-bilirubin grading has been shown to better predict overall survival in HCC patients receiving treatments like regorafenib[68]. For the assessment of hepatic fibrosis progression in patients with NAFLD, the fibrosis-4 index and NAFLD fibrosis score have emerged as essential diagnostic tools. These sophisticated scoring systems integrate multiple parameters, including hepatic function indicators, thrombocyte counts, and patient age, to determine fibrosis severity with particular relevance for oncological patients[69].

Cytokines such as transforming growth factor-beta and platelet-derived growth factor (PDGF) are integral to liver fibrosis and cirrhosis development. Elevated levels of these cytokines can indicate an increased risk of liver fibrosis. The PDGF signaling pathway, which is mediated through PDGF-α and PDGF-β receptors, is closely linked to fibrosis pathogenesis. Experimental models have shown that blocking these pathways can reduce fibrosis[70,71]. A 2024 study revealed that transforming growth factor-beta plays pivotal roles not only in liver fibrosis but also in liver repair and regeneration following cancer therapy[72]. In HCC, circulating tumor DNA (ctDNA) and circulating tumor cells serve as prognostic biomarkers. CtDNA quantification provides insights into tumor burden and reveals crucial genetic alterations, particularly in the TP53 or CTNNB1 genes, which potentially influence patients’ prognosis. Compared with conventional imaging methodologies, longitudinal ctDNA monitoring enables earlier detection of hepatic injury or tumor recurrence. This noninvasive approach offers real-time insights into the genetic landscape of tumors, aiding treatment decisions and improving outcomes[73-75].

Therapeutic response biomarkers

The identification and utilization of biomarkers for assessing hepatic response to cancer therapy remain crucial for therapeutic optimization, given the heterogeneous nature of individual treatment responses. Contemporary imaging modalities and serological assessments, while informative regarding treatment efficacy, frequently demonstrate delayed manifestation and may not provide early indicators of hepatic response. Immunotherapy, especially PD-1/PD-L1 and CTLA-4 inhibitors, has become a significant part of cancer treatment, but immune-related hepatitis has emerged as a clinical challenge. Studies have shown that hepatic T-cell infiltration and the depletion of regulatory T cells correlate significantly with the occurrence of irAEs, whereas T-cell activation status serves as a crucial biomarker for predicting liver response to immunotherapy[76].

Metabolic biomarkers also play important roles in evaluating the liver response to cancer therapy. Cancer treatments can disrupt liver metabolism, and measuring the levels of bile acids, fatty acid metabolites, and other metabolic products can help assess the tolerance of the liver. Metabolomic analysis provides comprehensive insights into the molecular mechanisms underlying hepatic injury and regeneration[77-79]. The future landscape of cancer treatment monitoring lies in multi-omics integration (genomics, transcriptomics, proteomics, and metabolomics), offering increased precision in managing hepatic diseases and cancer treatment. For example, multi-omics research in liver cancer has identified key biomarkers, such as ctDNA, noncoding RNAs, and specific proteins, which can serve as diagnostic and prognostic markers. Integrated metabolomics has revealed changes in bile acid and fatty acid metabolism that are critical for assessing liver function during and after treatment. As multi-omics research advances and computational tools are improved, these datasets can be integrated and analyzed to enable more personalized treatment strategies, ultimately increasing patient survival rates and improving treatment efficacy[80,81].

HEPATOPROTECTIVE STRATEGIES IN CANCER THERAPY

Hepatotoxicity represents a prevalent and significant adverse effect of cancer therapy, potentially compromising treatment tolerance and efficacy. With the evolution of cancer treatment modalities, hepatic toxicity has been highlighted as a critical therapeutic challenge. Consequently, hepatoprotective strategies encompassing pharmacological prophylaxis, individualized treatment modifications, and interdisciplinary collaborative approaches, have gained paramount importance, and these strategies are all aimed at minimizing hepatic injury, improving treatment tolerability, and optimizing therapeutic outcomes.

Drug prevention and intervention measures

Hepatoprotective agents play a crucial role in preventing and alleviating liver damage during cancer treatment. NAC, a potent antioxidant compound, demonstrates significant efficacy through augmentation of hepatic glutathione concentrations, subsequently attenuating oxidative stress-induced hepatocellular damage[82]. Clinical evidence substantiates NAC’s protective capabilities against hepatotoxicity caused by platinum-based compounds such as cisplatin[83]. Furthermore, NAC has been shown to reduce chemotherapy-associated transaminase elevations and significantly lower the risk of liver failure in later stages of chemotherapy[84].

UDCA represents another crucial hepatoprotective agent, predominantly utilized in cholestatic hepatopathies. Through enhancement of biliary secretion and cholangiocyte protection, UDCA effectively mitigates bile-mediated hepatic injury[85,86]. In cancer patients, UDCA is frequently used to prevent and treat cholestasis caused by immunotherapy and other anticancer therapy[87]. Other antioxidants, such as silymarin (extracted from milk thistle) and glycyrrhizin (derived from licorice root), also show protective effects against cancer therapy-related liver damage. Silymarin, a flavonoid complex with antioxidant and anti-inflammatory properties, stabilizes hepatocyte membranes, reduces lipid peroxidation, and promotes liver regeneration[88,89]. Similarly, glycyrrhizin has anti-inflammatory and hepatoprotective properties, effectively reducing drug-induced liver damage, particularly in chemotherapy settings. It helps regulate immune responses and alleviate oxidative stress in the liver, thereby minimizing liver damage caused by cancer treatments[89].

Dose adjustments and personalized treatment plans

The implementation of individualized therapeutic strategies and dose modifications for patients with hepatic dysfunction represents a critical component in optimizing cancer treatment outcomes. Patients with compromised hepatic function frequently exhibit significantly altered drug metabolism and reduced therapeutic tolerance, necessitating precise dose adjustments based on hepatic functional parameters. Chemotherapeutic agents, including cisplatin, oxaliplatin, and doxorubicin, demonstrate prolonged metabolism in hepatically impaired patients, potentially resulting in drug accumulation and enhanced hepatotoxicity[90,91]. While patients with Child-Pugh A may tolerate modified chemotherapy dosing under careful hepatic monitoring, those with Child-Pugh B or C face substantially elevated risks of adverse hepatic events due to severely compromised metabolic capacity, potentially precipitating multi-organ dysfunction.

Targeted therapies, particularly TKIs, require careful dose optimization in hepatically compromised patients. Research demonstrates altered pharmacokinetics of agents such as imatinib and sunitinib in hepatic impairment, necessitating dose modifications based on hepatic functional status[26]. Similarly, the use of ICIs, such as PD-1/PD-L1 inhibitors, requires careful consideration in patients with liver dysfunction. In cases of significant liver deterioration, dose reductions or treatment cessation may be necessary, with close monitoring of liver enzymes and immunosuppressive therapy to manage severe toxicity[27]. Personalized therapeutic approaches additionally incorporate pharmacogenomic considerations, with documented variations in cytochrome P450 enzymatic mutations significantly impacting drug metabolism and toxicity risk[92,93]. Tailoring dose adjustments using genetic testing can help reduce liver-related adverse effects and improve patient tolerance[94].

Multidisciplinary collaborative treatment strategies

The implementation of hepatoprotective strategies encompasses a comprehensive approach beyond pharmacological interventions, necessitating MDT collaboration in cancer management. The integration of therapeutic agents, nutritional optimization, and systematic liver function monitoring has demonstrated substantial efficacy in mitigating hepatic injury risks while enhancing therapeutic outcomes.

Nutritional support is an essential component of hepatoprotection. Due to the side effects of cancer treatment and malnutrition, patients may experience decreased liver metabolism and repair capacity. Therefore, a high-protein, low-fat diet, along with essential amino acid supplementation, can enhance liver repair. Furthermore, antioxidant supplementation, including vitamin E, vitamin C, and selenium, has exhibited beneficial effects in attenuating hepatic oxidative stress and inflammatory responses[95]. Liver function monitoring is critical for early detection of liver damage and for adjusting treatment strategies accordingly. Regular assessment of serum transaminases, bilirubin, and coagulation function is essential. Non-invasive tools like transient elastography are also employed to assess liver fibrosis, especially in patients undergoing long-term chemotherapy or targeted therapy[96]. One of the key point of optimal therapeutic outcomes lies in effective MDT collaboration. The coordinated expertise of oncologists, hepatologists, clinical nutritionists, and pharmaceutical specialists is essential in therapeutic decision-making to achieve optimal tumor control while minimizing hepatic complications[13,97]. In certain cases, liver transplantation may become the final option for patients with liver failure, particularly in cases of HCC or severe cirrhosis[98,99].

CURRENT CHALLENGES AND FUTURE DIRECTIONS

Despite considerable advancements in cancer therapy-related hepatoprotective strategies, significant challenges persist. A primary limitation in hepatoprotection stems from incomplete comprehension of the mechanisms of cancer therapy-induced hepatic injury. While the hepatotoxic potential of chemotherapeutic agents, targeted therapeutics, and immunotherapies is well-documented, the precise metabolic pathways and inflammatory cascades underlying hepatotoxicity remain incompletely characterized. For example, while ICIs are known to induce irAEs, the exact molecular mechanisms of immune-mediated liver injury, such as the roles of T cells and cytokines, are still not fully elucidated and require further experimental validation[100]. In addition, the hepatic consequences of emerging therapeutic modalities present significant concerns. The advent of cellular therapeutics, exemplified by CAR-T cell therapy, and genetic interventions has raised questions regarding potential hepatotoxicity. Despite targeted design principles, these novel approaches may inadvertently induce hepatic injury, particularly in patients with preexisting hepatic dysfunction[101-103]. However, there is currently limited data on the long-term effects of these novel therapies on liver health, highlighting the need for further investigation.

Given these limitations, future research priorities should address several critical domains to enhance hepatoprotection in cancer therapy. Firstly, large-scale, multi-center clinical trials are essential for validating hepatoprotective interventions. These comprehensive studies should systematically evaluate the hepatic impact of diverse cancer therapeutic modalities, generating robust evidence for protocol optimization. These trials should not only include various tumor types and treatment regimens but also consider high-risk populations with chronic liver disease, to better understand the full spectrum of treatment-related liver damage. Secondly, the validation of biomarkers is another critical area of future research. Although several potential biomarkers for early liver damage detection and prognosis prediction have been identified in recent years, their clinical application remains limited. Therefore, future studies should aim to further validate the sensitivity and specificity of these biomarkers, particularly in cancer patients. Liquid biopsy-based biomarkers, such as ctDNA and exosomes, may prove to be valuable tools for early diagnosis and real-time monitoring of liver injury. Lastly, the widespread adoption of immunotherapeutic agents, notably PD-1/PD-L1 and CTLA-4 inhibitors, has heightened concerns regarding irAEs. Contemporary research priorities should encompass the development of robust predictive algorithms for identifying patients at elevated risk of immune-mediated hepatitis. Additionally, investigations into optimized combination therapeutic approaches must be conducted to minimize hepatic complications while maintaining therapeutic efficacy.

CONCLUSION

Oncohepatology emerges as a critical interdisciplinary field linking oncology with hepatology, primarily focusing on liver injury resulting from contemporary cancer therapies. These hepatotoxic events arise through diverse mechanisms, including but not limited to direct cytolytic damage, metabolic disruption of hepatic cells, and ICI-related hepatitis. Especially, patients suffering from preexisting chronic liver diseases are at heightened risk of hepatic injury. To address these challenges, emerging biomarkers show promise in enabling early detection of subclinical injury, and management protocols require integrative strategies combining hepatoprotectants, clinician-guided dose optimization, and MDT interventions, collectively aiming to balance oncological efficacy with safety.