Psychological Stress in Hepatocellular Carcinoma: Clinical Outcomes and Biological Mechanisms

Abstract

Psychological stress is common among patients with hepatocellular carcinoma (HCC) and may influence the disease course beyond its effects on quality of life. However, whether stress contributes to tumor recurrence and survival, and through which biological pathways, remains uncertain. In this Review, we summarize clinical evidence linking anxiety, depression, and chronic stress with peri-treatment recovery and oncologic outcomes in HCC. We then examine how activation of the hypothalamic pituitary adrenal axis and sympathetic nervous system reshapes tumor and liver biology through neuroendocrine signaling, immune suppression, stromal remodeling, and metabolic reprogramming. We also review emerging mechanisms involving kynurenine metabolism, gut microbial metabolites, bile acids, mitochondrial dysfunction, and ferroptosis resistance. Finally, we discuss psychological and pharmacological interventions, ongoing clinical studies, and the methodological challenges that currently limit causal inference. Integrating longitudinal psychological assessment with circulating and tissue-based biomarkers will be essential to determine whether stress reduction can improve liver-related and oncologic outcomes in HCC.

Introduction

Hepatocellular carcinoma (HCC) accounts for approximately 80% of primary liver cancers and remains a leading cause of cancer-related death worldwide.^1–3 In 2022, an estimated 866,000 new cases of liver cancer and 759,000 deaths occurred globally.^1,4–6 The close correspondence between incidence and mortality highlights the substantial global burden of liver cancer.^7–9 Local ablation, transarterial therapies, molecularly targeted agents, and immune checkpoint inhibitors have expanded the treatment options for HCC.^10–16 Nevertheless, outcomes remain determined by tumor burden, underlying liver disease, hepatic reserve, and treatment tolerance. HCC usually develops through a multistep process in a chronically injured liver.¹⁷ Persistent inflammation and repeated cycles of hepatocyte injury and regeneration promote fibrosis and cirrhosis, genomic and epigenetic alterations, clonal expansion, angiogenesis, and progressive immune and metabolic remodeling. Major etiological conditions, including chronic hepatitis B or C virus infection, alcohol-related liver disease, and metabolic dysfunction-associated steatotic liver disease, converge on several tumor-promoting processes, such as oxidative stress, fibrogenic activation, immune dysfunction, and metabolic reprogramming.^18,19 At the molecular level, aberrant Notch signaling has been associated with distinct immune landscapes and prognosis in HCC. Other emerging pathways include PAQR3–TGF-β regulation of metastasis and ferroptosis, SOX4-associated immune suppression and sorafenib resistance, and YARS1–YAP1 signaling that promotes malignant progression.^20–23 Hepatitis B virus may additionally promote carcinogenesis through viral integration and direct oncogenic effects, including in the absence of cirrhosis. Consequently, HCC progression reflects interactions among malignant hepatocytes, the chronically diseased liver, stromal cells, and the immune microenvironment.²⁴ Patients must also contend with tumor progression, repeated surveillance for recurrence, worsening liver function, repeated treatment, and uncertainty about treatment benefit. Psychological factors may therefore represent an important but long-overlooked component of the HCC disease course because stress-responsive neuroendocrine and immune pathways may act on both tumor biology and the underlying liver disease.^25–27

Depression, anxiety, and cancer-related psychological distress are common among patients with HCC.²⁸ A systematic review and meta-analysis of 17 studies involving more than 60,000 patients estimated that approximately one quarter of patients with HCC had depression and one fifth had anxiety. Considerable heterogeneity was present across assessment instruments, disease stages, and treatment settings.²⁹ A systematic review of hepatobiliary malignancies also found that psychological distress was associated with poorer quality of life, sleep disturbance, and greater symptom burden. It may also impair social functioning, engagement with treatment, and long-term adaptation to illness.³⁰ Psychological stress should not be viewed only as an emotional response to a cancer diagnosis. Transient acute stress is usually reversible. Sustained or recurrent psychological stress can cause prolonged activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. This response can disrupt endocrine regulation, immune balance, and metabolic homeostasis. Psychological stress may therefore induce systemic responses with persistent biological effects.^31–33

Clinical evidence remains limited, but an increasing number of studies suggest that psychological status may be associated with oncologic outcomes in HCC. Among patients undergoing liver resection, higher anxiety scores and serum catecholamine concentrations were independently associated with shorter overall survival and time to recurrence.³⁴ More recent studies reported shorter disease-free survival and overall survival in patients with higher chronic stress after curative treatment. Higher pretreatment anxiety scores were also associated with a greater risk of death in patients with portal vein tumor thrombus who received hepatic arterial infusion chemotherapy.^35,36 Psychiatric disorders, the cumulative physiological burden of social adversity, and limited health literacy have also been associated with poorer survival in HCC.^37,38 Most available studies are single-center investigations with small samples or retrospective designs. Psychological status is also strongly influenced by tumor stage, impaired liver function, physical symptoms, and disease progression. It remains uncertain whether psychological stress independently affects prognosis or primarily reflects disease severity and overall vulnerability.

Experimental studies now provide a more coherent biological basis for the association between psychological stress and HCC progression. Chronic stress can reduce major histocompatibility complex class I expression and increase PD-L1 expression through beta-adrenergic signaling. These changes weaken immune recognition of tumor cells and promote immune escape.³⁹ Recent work showed that psychological stress disrupts hepatocyte ADRB2-QPRT signaling. This change diverts kynurenine metabolism away from NAD+ synthesis and promotes kynurenic acid accumulation. It also impairs mitochondrial function and effector activity in hepatic CD8+ T cells.⁴⁰ Stress can also disturb hepatic homeostasis through ADRB2-related signaling and accelerate experimental hepatocarcinogenesis.⁴¹ Stress-associated changes in the gut microbiota and indole-3-propionic acid can alter communication between endothelial cells and macrophages. Taurocholate-driven CBX5-MYC-PHGDH signaling promotes serine metabolism and suppresses ferroptosis, thereby supporting HCC growth.^42–44 Neuroendocrine activation, immunosuppression, and metabolic reprogramming are therefore not independent events. They form mutually reinforcing circuits among hepatocytes, tumor cells, stromal cells, and immune cells. HCC generally develops in a liver affected by chronic inflammation, fibrosis, and metabolic dysfunction. Psychological stress may therefore act on the tumor, the nonmalignant liver, hepatic functional reserve, and the local immune environment. This combined effect on the tumor and liver is a defining feature of stress biology in HCC (Figure 1).

Figure 1.

Integrated framework linking psychological stress to hepatocellular carcinoma progression. Psychological stressors in patients with hepatocellular carcinoma include cancer diagnosis, concerns about recurrence or metastasis, and repeated treatment. These stressors induce systemic stress responses and activate neuroendocrine pathways. Key mechanisms include β-adrenergic signaling, glucocorticoid and PD-1 signaling, brain to liver neural circuits, hepatic stellate cell activation, and stromal remodeling. Neuroendocrine activation interacts with metabolic reprogramming and remodeling of the tumor microenvironment, thereby promoting tumor growth, immune escape, invasion, recurrence, and metastasis. This framework also highlights potential clinical applications, including risk stratification, psychosocial intervention, and pharmacological modulation.

Abbreviations: HCC, hepatocellular carcinoma; PD-1, programmed cell death protein 1; TME, tumor microenvironment.

Previous psycho-oncology studies and reviews have primarily described the prevalence of depression and anxiety, psychosocial needs, impaired quality of life, and supportive-care interventions in patients with HCC.^30,45,46 Conversely, reviews of stress-related cancer biology have generally examined multiple tumor types or individual neuroendocrine pathways without considering the distinctive biological context of HCC, in which malignant progression occurs alongside chronic inflammation, fibrosis, cirrhosis, and impaired hepatic reserve. Consequently, three important knowledge gaps remain. First, the extent to which psychological stress is associated with HCC recurrence and survival, rather than only quality of life and symptom burden, has not been clearly established. Second, clinical observations have not been systematically integrated with HCC-specific neuroendocrine, immune, stromal, and metabolic mechanisms. Third, the translational readiness of psychological assessment, circulating biomarkers, and stress-targeted interventions has not been critically evaluated. To address these gaps, this Review integrates clinical observational evidence with preclinical and translational studies, while explicitly distinguishing established human associations from mechanistic hypotheses derived from experimental models. We first summarize the relationships between psychological stress, peri-treatment outcomes, recurrence, and survival in HCC. We then examine three interconnected biological domains: neuroendocrine activation, remodeling of the immune microenvironment, and metabolic reprogramming. Finally, we evaluate psychological and pharmacological interventions, ongoing clinical studies, and the methodological requirements for determining whether stress reduction can improve liver-related or oncologic outcomes. This framework is intended to define the current limits of evidence and provide a basis for longitudinal, biomarker-integrated, and mechanism-informed research in HCC.

Clinical Evidence Linking Psychological Stress to Outcomes in HCC

Clinical studies have examined the associations between psychological stress and HCC outcomes at two broad levels: peri-treatment outcomes, including pain, sleep, quality of life, and recovery during hospitalization; and longer-term oncologic outcomes, including recurrence, disease progression, and overall survival. Associations with short-term patient-reported outcomes have been relatively consistent, whereas evidence for recurrence and survival remains based largely on a limited number of observational studies (Table 1).

Table 1.

Psychological Stress and Clinical Outcomes in HCC

Study	Population	Stress Measure	Main Finding
Lee HH et al, 201947	410 patients undergoing hepatectomy	Preoperative anxiety and depression	Poorer quality of life during 2-year follow-up
Liu J et al, 201734	110 patients undergoing curative hepatectomy	HAMA and serum catecholamines	Higher anxiety and catecholamine levels were associated with shorter OS and time to recurrence
Wang X et al, 202535	90 patients after curative treatment	PSS-10, heart rate variability, and hair cortisol	High chronic stress was associated with shorter DFS and OS
Tan HY et al, 202536	68 patients with PVTT receiving HAIC	Pretreatment anxiety	Higher anxiety was associated with increased mortality, but not with ORR or PFS
Abad SE et al, 202638	139 patients with HCC	Allostatic load and health literacy	Higher allostatic load and lower health literacy were associated with increased mortality
Huang KL et al, 202348	Nationwide HCC cohort	Antidepressant use	Postdiagnosis use was associated with lower overall and cancer-specific mortality

Abbreviations: DFS, disease-free survival; HAIC, hepatic arterial infusion chemotherapy; HAMA, Hamilton Anxiety Rating Scale; HCC, hepatocellular carcinoma; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PSS-10, 10-item Perceived Stress Scale; PVTT, portal vein tumor thrombosis.

Psychological Stress and Peri-Treatment Outcomes

Anxiety and depression may be present before HCC treatment and can continue to affect functional status and quality of life after treatment. In a multicenter prospective study of 410 patients undergoing liver resection for HCC, the prevalences of preoperative anxiety, depression, and coexisting anxiety and depression were 9.0%, 17.1%, and 7.1%, respectively. At 6 months, 1 year, and 2 years after surgery, patients with anxiety or depressive symptoms at baseline had persistently lower scores across all domains of the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-H), with between-group differences widening over time.⁴⁷ These findings suggest that perioperative psychological symptoms are not merely transient reactions to diagnosis and may continue to influence long-term recovery.⁴⁹

Psychological burden may also vary across treatment settings. A cross-sectional study of 101 patients with HCC compared psychological status among those receiving liver resection, radiofrequency ablation, transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), or immunotherapy. Patients treated with TACE, HAIC, or immunotherapy generally reported greater symptom distress, anxiety, and depression, whereas those undergoing radiofrequency ablation had comparatively better overall quality of life.⁵⁰ Because treatment modality is closely related to tumor stage, liver function, and disease burden, these differences cannot be attributed to treatment alone. They more likely reflect a stress context jointly shaped by treatment intensity, disease severity, and physical symptoms.

Overall, clinical studies consistently associate anxiety and depression with poorer quality of life, sleep, and functional recovery. Evidence regarding pain, length of hospital stay, and treatment-related complications, however, comes primarily from intervention or nursing studies. Fatigue, insomnia, appetite loss, and impaired concentration, items commonly captured by psychological scales, overlap substantially with manifestations of cirrhosis, hepatic encephalopathy, and treatment toxicity. Psychological screening results should therefore be interpreted alongside liver function, cognitive status, and symptom burden.

Psychological Stress and Oncologic Outcomes

Far fewer studies have directly examined psychological stress in relation to HCC recurrence or survival than have assessed quality of life or symptom outcomes. An early prospective study enrolled 110 patients undergoing curative liver resection and assessed anxiety using the Hamilton Anxiety Rating Scale together with serum catecholamine measurements. Higher anxiety scores were associated with more advanced tumor stage and metastasis, and both anxiety scores and catecholamine concentrations were independently associated with shorter overall survival and time to tumor recurrence in multivariable analyses.³⁴ This study was the first in a clinical HCC population to link subjective anxiety, circulating stress hormones, and prognosis, providing preliminary translational support for a role of sympathetic activation in tumor progression.

A 2025 prospective cohort study evaluated chronic stress using subjective and objective measures. The study included 90 patients with HCC who had undergone curative liver resection or radiofrequency ablation. The assessment combined the 10-item Perceived Stress Scale (PSS-10), a heart rate variability-derived Stress Score, and hair cortisol concentration into a composite chronic stress index. The cutoffs for the PSS-10 (15.3), Stress Score (50.0), and hair cortisol concentration (19.7 pg/mg) were selected using X-tile analysis according to disease-free survival within the same 90-patient cohort. Each variable was assigned 1 point below and 2 points above its cutoff; total scores of 3–4 and 5–6 defined the low- and high-stress groups, respectively. These thresholds were therefore data-driven and outcome-optimized rather than prespecified clinical cutoffs, which may limit their generalizability and require external validation. Median disease-free survival was 18 months in the high-stress group and 37 months in the low-stress group. The high-stress group also had a higher risk of recurrence or death (hazard ratio [HR], 2.42; 95% confidence interval [CI], 1.44 to 4.07). Overall survival was poorer in the high-stress group (HR, 2.00; 95% CI, 1.06 to 3.79).³⁵ A major strength was the use of repeated multimodal assessment rather than a single psychological scale. Stress measures were obtained at 1, 3, and 6 months after treatment. The sample was small, and some stress measures were obtained after curative therapy. Reverse causation from occult early recurrence or poor postoperative recovery cannot be excluded.

A similar survival signal has been reported in advanced HCC. In a propensity score-matched study of 68 patients with portal vein tumor thrombus receiving HAIC, objective response rate, progression-free survival (PFS), and treatment-related adverse events did not differ significantly between patients with high and low anxiety. In multivariable analysis, however, a higher pretreatment anxiety score was independently associated with a greater risk of death (HR, 2.769; 95% CI, 1.289–5.947).³⁶ Notably, the unadjusted comparison of overall survival between the matched groups was not statistically significant, and anxiety emerged as an independent factor only in the multivariable model. The result should therefore be interpreted cautiously in light of the small sample, limited number of events, and potential model instability.

Psychological scales are not the only potential source of prognostic information. The cumulative physiological burden caused by chronic psychosocial adversity may also be relevant. An exploratory analysis of 139 patients with HCC used six physiological indicators to construct an allostatic load score. One point was assigned for each of six biomarkers outside a prespecified clinical range, and the points were summed to produce the allostatic load score. High allostatic load was defined as a score of ≥3 using a modified previously validated index rather than an outcome-optimized cutoff derived from this HCC cohort. The primary survival analysis nevertheless modeled the score continuously and reported the hazard ratio per one-point increase. A higher score was associated with mortality (HR per unit increase, 1.27; 95% CI, 1.05 to 1.55).³⁸ Lower health literacy was also associated with a higher risk of death (HR, 1.83; 95% CI, 1.10 to 3.05). Allostatic load reflects the cumulative biological effects of long-term adversity across cardiovascular, metabolic, and inflammatory systems. It is not specific to psychological stress and may also reflect the severity of cirrhosis, metabolic comorbidity, and systemic frailty.

Taken together, observational studies have shown a broadly consistent association between psychological stress and HCC recurrence or mortality, with prognostic signals emerging from subjective anxiety, neuroendocrine measures, and cumulative physiological burden.⁵¹ These exposures are not interchangeable, however, and outcomes may be jointly influenced by tumor stage, liver function, symptom burden, treatment adherence, and social support. Importantly, death in HCC may result from tumor progression, hepatic decompensation, infection, or bleeding. Analyses restricted to overall survival cannot determine whether psychological stress primarily modifies tumor biology or instead marks global vulnerability. At present, psychological stress is therefore best regarded as a candidate prognostic marker that requires further validation rather than an established independent cause of adverse outcomes.

Interpretation of peripheral stress biomarkers requires caution. Hair cortisol is influenced by exogenous glucocorticoids, hair characteristics and cosmetic treatment, sampling methods, and altered cortisol metabolism in chronic liver disease. Heart rate variability-derived stress scores are affected by age, physical activity, arrhythmia, β-blocker use, sleep, pain, and cirrhosis-related autonomic dysfunction. Circulating kynurenine metabolites are additionally influenced by liver and renal function, systemic inflammation, infection, nutritional status, and the gut microbiota.^15,20,52,53 These measures reflect whole-body physiological processes and cannot identify the cellular source or spatial distribution of biological changes. None can therefore serve as a specific surrogate for intratumoral immune or metabolic alterations without paired tissue-based validation.^54–57

Biological Mechanisms Linking Psychological Stress to HCC Progression

Most mechanistic evidence linking psychological stress to HCC is derived from cell and animal studies, whereas direct clinical validation remains limited. These findings should therefore be interpreted as evidence of biological plausibility rather than established causal mechanisms in patients. The central nervous system first perceives and integrates psychological stress. The HPA axis, sympathetic nervous system, and autonomic innervation of the liver then translate stress into glucocorticoid, catecholamine, and local neurotransmitter signals.^58–60 Hepatocytes, HCC cells, hepatic stellate cells, and multiple immune-cell populations express adrenergic and/or glucocorticoid receptors, allowing sustained psychological stress to alter intrinsic malignant phenotypes, hepatic tissue homeostasis, and antitumor immunity simultaneously. Recent studies further indicate that stress-responsive neuroendocrine signals are amplified through intermediates such as kynurenine metabolites, bile acids, and microbiota-derived metabolites, ultimately forming an interconnected neuroendocrine-immune-metabolic regulatory network.^40,41,52,53 The major biological mechanisms linking psychological stress to HCC progression are summarized in Figure 2.

Figure 2.

Interconnected biological mechanisms linking psychological stress to hepatocellular carcinoma progression. Psychological stress activates the hypothalamic pituitary adrenal axis and disrupts hepatic homeostasis. It also promotes immunosuppressive remodeling of the tumor microenvironment through changes in lymphoid and myeloid cell populations and their associated cytokine networks. Concurrent metabolic reprogramming alters mitochondrial energy metabolism, glucose utilization, amino acid metabolism, nucleotide biosynthesis, and lipid synthesis. These neuroendocrine, immune, and metabolic changes interact to promote tumor progression and contribute to reduced survival.

Abbreviations: HPA, hypothalamic pituitary adrenal; ILC2, group 2 innate lymphoid cell; MDSC, myeloid derived suppressor cell; TME, tumor microenvironment; Treg, regulatory T cell.

Neuroendocrine Activation

The HPA Axis, Glucocorticoids, and HCC Progression

Sustained psychological stress activates the HPA axis, increasing the release of corticotropin-releasing hormone, adrenocorticotropic hormone, and glucocorticoids. In contrast to the direct effects of catecholamines on tumor-cell proliferation and migration, the protumor effects of glucocorticoids in HCC have been demonstrated primarily through suppression of antitumor immunity. In a chronic unpredictable mild stress model, depression-like mice showed accelerated liver tumor growth and increased circulating glucocorticoid concentrations; higher glucocorticoid levels were also observed in patients with liver cancer who had depressive symptoms. Mechanistic experiments showed that dexamethasone upregulated PD-1 on tumor-infiltrating natural killer (NK) cells and reduced NK-cell cytotoxicity through the PD-1/PD-L1 pathway. This effect was evident mainly in NK cells within the tumor microenvironment and was not prominent in peripheral blood or the spleen.⁵²

These findings suggest that stress-related glucocorticoids do not simply induce generalized immunosuppression, but may cause spatially selective dysfunction of NK cells within the tumor. Because NK cells are central to immune surveillance in virus-associated liver disease and HCC, glucocorticoid receptor-mediated upregulation of PD-1 may be particularly relevant in chronic hepatitis and cirrhosis. However, it remains unclear whether endogenous glucocorticoid exposure in patients is sufficient to reproduce these effects, and longitudinal studies jointly assessing glucocorticoid dynamics, NK-cell function, and survival in patients with HCC are lacking.⁵²

Sympathetic Nervous System, Catecholamines, and Adrenergic Receptor Signaling

Compared with the HPA axis, the sympathetic nervous system and β-adrenergic signaling constitute the most extensively studied stress-related pathway in HCC. Chronic stress increases the release of norepinephrine and epinephrine, which act on tumor cells, stromal cells, and immune cells through ADRB2 and downstream cAMP-protein kinase A, mitogen-activated protein kinase (MAPK), Src, and transcriptional networks.

In HCC cells, epinephrine and norepinephrine activate Src through ADRB2 and enhance the migration and invasion of Hep3B cells; knockdown of ADRB2 or pharmacologic inhibition of Src abrogates these effects, indicating that ADRB2-Src signaling can directly increase HCC-cell motility and invasiveness.⁶¹ A separate study showed that stress-induced epinephrine upregulated the deubiquitinase USP10 through ADRB2-c-Myc signaling. USP10 stabilized the transcription factor PLAGL2 by deubiquitination, whereas PLAGL2 in turn promoted USP10 transcription, establishing a USP10-PLAGL2 positive-feedback loop that drove HCC-cell proliferation, epithelial-mesenchymal transition, and tumor progression.⁶²

Hepatic Stellate Cell Mediated Stromal Remodeling

HCC typically develops in chronically inflamed and fibrotic livers enriched in activated hepatic stellate cells; the effects of psychological stress are therefore not confined to malignant cells. Norepinephrine activates hepatic stellate cells and induces secretion of secreted frizzled-related protein 1 (sFRP1). Conditioned medium from norepinephrine-treated stellate cells enhances HCC-cell proliferation, migration, invasion, epithelial-mesenchymal transition, and expression of cancer stemness markers. sFRP1 facilitates the interaction of Wnt16B with FZD7, activates β-catenin, and further induces Wnt16B expression, thereby creating a Wnt16B-β-catenin positive-feedback loop.⁵³

This mechanism is particularly relevant to HCC: rather than acting only on cancer cells, psychological stress can exploit pre-existing stellate-cell populations in the fibrotic liver and convert neurotransmitter signaling into sustained protumor paracrine activity. A 2025 study further showed that norepinephrine promoted hepatic stellate-cell activation through SRC, AKT, and ERK pathways, and that inhibition of this process attenuated HCC growth induced by chronic restraint stress, providing additional support for a sympathetic nervous system-stellate cell-HCC axis.⁶³

Brain to Liver Neural Circuits and Hepatic Homeostasis

Recent work has extended stress biology beyond circulating hormones to anatomically defined brain-liver neural circuits. Single-nucleus RNA sequencing showed that chronic restraint stress altered hepatocyte transcriptional programs. Programs supporting protein secretion, xenobiotic metabolism, and glucose homeostasis were reduced. In contrast, pathways involving fatty-acid metabolism, PPAR, AMPK, TGF-β, and coagulation were increased, together with lipid-metabolism genes and oncogenes. Stress accelerated tumor formation in several murine liver cancer models, whereas propranolol treatment or hepatocyte-specific deletion of Adrb2 attenuated this effect. In human HCC datasets, stronger ADRB2 signaling signatures were also associated with poorer overall and disease-free survival.⁴¹ These findings identify hepatocytes as important effector cells of brain-liver stress signaling, although the human data remain associative.

Brain–liver neural regulation may also influence hepatic regeneration. In a mouse model, chronic sleep deprivation impaired liver regeneration after hepatectomy through sympathetic norepinephrine signaling and macrophage ADRB2.⁶⁴ However, this nonmalignant model does not establish an effect of psychological stress on HCC recurrence.

Remodeling of the Immune Microenvironment

A central effect of psychological stress in HCC is to shift the immune microenvironment from immune surveillance toward immune escape. Complementary mechanisms have been identified in NK cells, CD8+ T cells, myeloid-derived suppressor cells, and macrophages.

NK-Cell Dysfunction

In depression-like mice bearing liver tumors, elevated glucocorticoid levels selectively upregulated PD-1 on tumor-infiltrating NK cells, strengthened PD-1/PD-L1 inhibitory signaling, and impaired NK-cell cytotoxicity. The change was largely confined to the tumor microenvironment rather than the peripheral immune compartment, indicating that stress-related immunosuppression may be both tissue- and cell-specific.⁵²

However, no clinical study has demonstrated that depression or elevated cortisol reduces the response to immune checkpoint inhibitors in patients with HCC. This mechanism therefore remains a preclinical hypothesis.

Impaired Antigen Presentation and PD-L1 Upregulation

Chronic restraint stress reduced MHC class I expression and increased PD-L1 protein levels in H22 liver tumors, creating a dual immune-evasion phenotype characterized by impaired tumor recognition and enhanced inhibitory signaling. Mechanistic experiments showed that β-adrenergic activation of MAPK signaling suppressed the STAT1-IRF1 pathway and reduced expression of MHC class I antigen-processing and presentation components, including LMP2, LMP7, TAP1, and TAP2. At the same time, increased phosphorylation of p38 MAPK and eIF2α promoted PD-L1 translation without a corresponding increase in PD-L1 mRNA.³⁹

These findings show that stress can alter the immune visibility of tumor cells rather than simply reducing T-cell abundance. MHC class I downregulation limits recognition of tumor antigens by CD8+ T cells, whereas PD-L1 upregulation further suppresses effector T cells that have entered the tumor. Propranolol partially restored MHC class I expression, reduced PD-L1, and inhibited stress-induced tumor growth, placing β-adrenergic signaling upstream of this combined immune-evasion program.³⁹

Mobilization and Recruitment of Myeloid-Derived Suppressor Cells

Myeloid-derived suppressor cells (MDSCs) are an important link between chronic stress and myeloid immunosuppression. In H22 tumor-bearing mice, chronic restraint stress promoted the mobilization of MDSCs from the bone marrow to the spleen and tumor, increased CXCR2 expression and ERK phosphorylation in bone marrow MDSCs, and upregulated CXCL5 in tumor tissue. In vitro, epinephrine and norepinephrine enhanced CXCR2-ERK signaling and the T-cell-suppressive activity of MDSCs, whereas corticosterone had no comparable effect. Propranolol reversed MDSC recruitment and tumor growth.⁶⁵

These results indicate two coordinated effects: catecholamines alter chemokine production by the tumor while simultaneously increasing MDSC responsiveness to CXCL5, establishing a CXCL5-CXCR2 recruitment axis driven from both the tumor and bone marrow. Because CXCL5 can also promote HCC-cell proliferation, invasion, and neutrophil infiltration and has been associated with recurrence and poor survival, stress-induced CXCL5 may exert both direct protumor effects and indirect myeloid immunosuppression.^65,66

A subsequent 2026 study likewise found that chronic stress reduced intratumoral CD4+ and CD8+ T cells and increased granulocytic and monocytic MDSCs and M2-like macrophages. Lowering norepinephrine levels or blocking β-adrenergic signaling partially restored these immune changes.⁶⁷ Although the agents used in that study may also have independent anti-inflammatory and antitumor effects, the findings are consistent with the CXCL5-CXCR2 study and support catecholamine-driven myeloid immunosuppression.

Hepatocyte Metabolic Dysfunction and CD8+ T-Cell Impairment

Suppression of CD8+ T cells under stress does not necessarily result from the direct action of glucocorticoids or catecholamines; it may also be mediated by hepatocyte metabolic dysfunction. Chronic stress disrupts hepatocyte ADRB2-QPRT signaling, diverts kynurenine metabolism, and reduces NAD+ availability, thereby impairing mitochondrial function, energy metabolism, and effector-molecule production in CD8+ T cells.⁴⁰ This work identifies nonimmune hepatocytes as a metabolic relay for stress-associated immunosuppression, showing that psychological stress can first alter the hepatic tissue environment and only then induce T-cell dysfunction.

Communication Between Endothelial Cells and Macrophages

Stress-related immune remodeling may also be mediated through the tumor vascular niche. Changes in microbial metabolites can regulate endothelial adhesion and endothelial-macrophage communication, thereby affecting the recruitment, spatial distribution, and functional state of myeloid cells. This observation extends the immune effects of psychological stress beyond intracellular signaling within immune cells to the vascular-stromal interface. However, the implicated ligand-receptor interactions are based mainly on single-cell communication inference and preclinical interventions and require validation in cell type-specific genetic models.⁴²

Metabolic Reprogramming

The liver is the central organ for carbohydrate, lipid, amino acid, bile acid, and xenobiotic metabolism. It also provides the tissue context in which HCC develops. Psychological stress therefore has a distinctive effect in HCC because the nonmalignant liver participates in the response. Stress can reprogram cancer-cell metabolism. It can also alter hepatocytes and the hepatic microenvironment before acting on the tumor. These changes may create a metabolic environment that favors tumor initiation and progression.

The Kynurenine Pathway and NAD+ Metabolism

The tryptophan-kynurenine pathway has long been linked to immunosuppression, but recent HCC research suggests that the critical event may not simply be tryptophan depletion or kynurenine accumulation. Instead, reduced hepatocyte QPRT redirects pathway flux. Chronic stress diverts kynurenine metabolism away from de novo NAD+ synthesis toward kynurenic acid accumulation, leading to mitochondrial and effector dysfunction in CD8+ T cells.⁴⁰

QPRT may therefore function not merely as a metabolic enzyme but as a stress-responsive hepatic immunometabolic checkpoint. Kynurenic acid, NAD+, and their ratio are potential markers of stress-associated metabolic alterations, but their circulating levels cannot be assumed to reflect hepatocyte QPRT activity or intratumoral CD8+ T-cell dysfunction because they are influenced by systemic inflammation, hepatic and renal function, nutritional status, and whole-body tryptophan metabolism. Human tissue data, however, remain correlational, and it has not been shown that psychological stress drives HCC recurrence or resistance to immunotherapy through this pathway in patients.⁴⁰

Gut Microbiota, IPA, and the Vascular Immune Niche

Chronic stress can alter intestinal barrier function, microbial composition, and microbial metabolism through bidirectional gut-brain signaling.^68–70 In HCC models, depletion of Phocaeicola vulgatus (P. vulgatus) and reduced indole-3-propionic acid (IPA) were associated with accelerated tumor growth, whereas restoration of the bacterium or supplementation with IPA suppressed tumor progression. The downstream effect was not direct inhibition of HCC-cell proliferation. Rather, reduced endothelial JAM2 and weakened JAM2-F11R-mediated endothelial-macrophage communication remodeled the tumor vascular immune niche.⁴²

This study links psychological stress, the gut microbiota, tryptophan metabolism, and the tumor immune microenvironment in a multistep stress-microbiota-metabolite-endothelial cell-macrophage axis. Compared with descriptive fecal microbiome analyses, causal inference is strengthened by bacterial reconstitution and metabolite supplementation. IPA, however, has broad antioxidant, barrier-protective, and immunomodulatory actions, and JAM2-F11R signaling may represent only one component of its effects. In addition, the human analyses mainly identified stress-associated microbial features and did not establish that microbiome changes in patients with HCC were caused by psychological stress.⁴²

Bile Acid Reprogramming and Ferroptosis Resistance

Bile acids are metabolites and signaling molecules with particular relevance to liver biology. A 2026 study combined data from CHARLS, NHANES, and the UK Biobank with patient samples, multi-omics analyses, and a mouse model of social isolation. Depression was associated with a higher risk of HCC in population-based cohorts, while social isolation was used as an experimental model of psychological stress. Taurocholate was identified as a key metabolite that was increased in stress-associated HCC.⁴³

Mechanistically, taurocholate weakened the interaction between chromobox protein 5 (CBX5) and an E3 ubiquitin ligase, reducing CBX5 ubiquitination and degradation and thereby increasing its stability. Stabilized CBX5 cooperated with MYC at the PHGDH promoter to enhance PHGDH transcription. PHGDH is the rate-limiting enzyme in de novo serine synthesis; its upregulation reduced lipid peroxidation and rendered HCC cells less sensitive to ferroptosis, ultimately promoting tumor growth. Knockdown of CBX5, MYC, or PHGDH attenuated the protumor effect of taurocholate.⁴³

These findings connect stress-associated bile-acid changes with serine metabolism and ferroptosis resistance. However, the human data remain associative and do not establish taurocholate as a mediator of stress-related HCC progression or support ursodeoxycholic acid as an antitumor treatment.⁴³

Mitochondrial Oxidative Phosphorylation and Disruption of Hepatocyte Zonation

Studies of the nonmalignant liver provide additional supportive evidence beyond direct HCC models.^71,72 A 2026 single-cell study showed that chronic restraint stress caused hepatocyte vacuolar degeneration, elevated aminotransferases, apoptosis, and mitochondrial structural abnormalities and suppressed oxidative phosphorylation in hepatocytes. The effect was especially pronounced in periportal zone 1 hepatocytes and was characterized by reduced PI3K-AKT signaling, activation of FoxO3a, and epigenetic silencing of genes involved in oxidative phosphorylation.⁷³

Because this study did not use an HCC model, the findings show only that psychological stress can alter hepatocyte energy metabolism and zonation before tumor development. In HCC arising in cirrhosis, metabolic dysfunction-associated steatotic liver disease (MASLD), or viral liver disease, persistent mitochondrial injury could conceivably promote a carcinogenic milieu through oxidative stress, hepatocyte death, and compensatory proliferation. This hypothesis requires direct testing in HCC models with underlying liver disease and in longitudinal patient samples.⁷³

Lipid Metabolism and Stress-Related Hepatic Susceptibility

The effects of prolonged stress on hepatic lipid metabolism cannot be explained only by sustained sympathetic activation. Chronic stress increases circulating norepinephrine, but it can also cause degeneration of hepatic sympathetic nerve terminals. It can reduce beta3-adrenergic receptor expression and blunt cAMP responses. These changes produce hepatic catecholamine resistance and lipid accumulation. Inhibition of the relevant central projections, interruption of sympathetic input to the liver, or activation of beta3 receptors ameliorated steatosis.⁷⁴ This evidence comes from the nonmalignant liver. It suggests that prolonged stress may increase hepatic susceptibility through receptor remodeling and metabolic dysregulation.

Consistent with this concept, HCC models show that chronic stress activates hepatocyte programs involving fatty-acid metabolism, PPAR, AMPK, TGF-β, and coagulation and increases oncogene expression; hepatocyte-specific deletion of Adrb2 suppresses stress-accelerated hepatocarcinogenesis.⁴¹ Together, these studies suggest that stress responses are cell type- and time-dependent. ADRB2 activation in tumor cells or hepatic stellate cells can promote tumor progression, whereas prolonged exposure in nonmalignant hepatocytes may lead to receptor desensitization, lipid deposition, and tissue injury.

Translational Limitations of Preclinical Stress Models

Preclinical models provide important evidence for causal links between stress exposure and HCC progression, but their translation to human psychological stress remains limited.⁷⁵ Restraint stress and social isolation usually involve standardized stressors of predefined intensity and duration, whereas patients with HCC experience heterogeneous and fluctuating stress related to diagnosis, recurrence risk, physical symptoms, repeated treatment, financial burden, and impaired liver function.^{19,21–23,28,29,32,34,36–38} Human responses are also modified by coping strategies, social support, psychiatric history, and individual neuroendocrine resilience, which cannot be adequately reproduced in homogeneous laboratory animals. These models should therefore be viewed as tools for establishing mechanistic plausibility rather than direct representations of human stress exposure. Their findings require validation through longitudinal studies combining repeated psychological assessment with neuroendocrine, immune, metabolic, and tumor-tissue measurements in patients with HCC.

Therapeutic and Clinical Implications

The potential clinical applications of research on psychological stress in HCC should be divided into two categories: supportive-care measures that can be implemented in current practice and disease-modifying strategies that remain investigational. Current evidence supports incorporating psychological assessment and symptom-directed intervention into multidisciplinary HCC care to identify anxiety, depression, sleep disturbance, pain, impaired coping, and barriers to treatment adherence. By contrast, the use of psychological status or stress-related biomarkers to select anticancer treatment, predict treatment response, or modify oncologic surveillance remains unsupported. Similarly, whether psychological or pharmacological modulation of stress-responsive pathways can reduce recurrence or prolong survival requires prospective validation.

Psychological and Behavioral Interventions

Mindfulness-based and cognitive behavioral interventions are the most extensively studied psychological approaches in HCC. Randomized studies have shown that guided self-help mindfulness reduces psychological distress and improves sleep quality and quality of life, with part of the effect mediated by lower perceived stress and greater psychological flexibility.⁷⁶ A blended offline-online cognitive behavioral stress-management program likewise reduced anxiety and depression after HCC surgery and improved mental health and functional quality of life.⁷⁷

In the interventional oncology setting, mindfulness-based stress reduction added to usual care was associated with lower pain after TACE, reduced use of rescue analgesia and less frequent analgesic escalation, greater self-efficacy, a lower incidence of postembolization syndrome, and shorter hospital stay.⁷⁸ Because allocation was retrospective, however, the findings may have been influenced by differences in pain management, nursing intensity, and discharge decisions. They do not establish that mindfulness directly attenuates TACE-induced tissue injury or inflammation.

Psychological interventions have shown early and reasonably consistent benefits for mood, sleep, pain, and quality of life in patients with HCC. Most studies have had short follow-up and have focused on patient-reported outcomes. No study has established that psychological intervention reduces recurrence or prolongs survival. A 2026 meta-analysis included 32 randomized trials and 5704 patients with cancer. It suggested a small survival benefit from psychosocial interventions. However, the prediction interval included no effect, and heterogeneity across cancer types and intervention formats was substantial. These findings cannot be applied directly to HCC.⁷⁹

Psychological interventions should currently be positioned as components of supportive HCC care.^80–83 Their established role is to address psychological symptoms and improve patient-reported outcomes, whereas their effects on recurrence and survival remain unproven. The practical implementation of psychological assessment within HCC management is discussed below.

Pharmacologic Targeting of Stress-Responsive Pathways

Antidepressants should be used for clinically indicated depressive or anxiety disorders rather than as antitumor agents for HCC. A nationwide cohort study found that antidepressant use after HCC diagnosis was associated with lower all-cause and cancer-specific mortality.⁴⁸ This association may reflect improved psychological symptoms, better treatment adherence, closer medical follow-up, or healthy-user effects, and randomized evidence that antidepressants reduce HCC recurrence or prolong survival is lacking.

β-Adrenergic receptor blockade has a strong mechanistic rationale because β-adrenergic signaling promotes HCC-cell invasion, hepatic stellate-cell activation, recruitment of myeloid suppressor cells, and impaired antigen presentation. Some retrospective studies have suggested that propranolol may improve overall survival in unresectable or metastatic HCC, but a reduction in recurrence after curative treatment has not been consistently observed.⁸⁴ Among patients with advanced HCC receiving immune checkpoint inhibitors, β-blocker use was not significantly associated with overall survival, PFS, or objective response rate.⁸⁵

These studies are highly susceptible to confounding by portal hypertension, liver function, blood pressure, and treatment indication. Routine β-blocker use solely for antitumor purposes or to attenuate psychological stress is therefore not supported. A more plausible translational strategy would be prospective, biomarker-guided evaluation in patients with high sympathetic activity, specific adrenergic receptor profiles, or stress-associated immune phenotypes.

Ongoing Prospective Studies and Clinical Trials

Several prospective studies are now systematically evaluating the relationship between psychological stress, treatment response, and long-term outcomes in HCC. This shift marks an important transition from single-center retrospective associations toward multicenter cohorts, repeated psychological assessment, and interventional research (Table 2).

Table 2.

Ongoing or Registered Clinical Studies of Psychological Stress in HCC

Study	Setting	Focus
NCT07141056	HCC receiving immunotherapy	Stress, immune markers, PFS/DFS
NCT07325565	HCC and ICC cohorts	Distress, sleep, treatment outcomes
NCT07436845	HCC receiving HAIC-based therapy	Anxiety, immune markers, survival
ChiCTR2500114790	Advanced HCC treated with lenvatinib	Emotional stress and treatment response
NCT06541990	Newly diagnosed HCC	Psychoeducation and distress
NCT05942560	Liver cancer with anxiety or depression	CBT, immune function, survival
NCT06938945	HCC receiving immunotherapy	ePRO monitoring and quality of life

Abbreviations: CBT, cognitive behavioral therapy; DFS, disease-free survival; ePRO, electronic patient-reported outcome; HAIC, hepatic arterial infusion chemotherapy; HCC, hepatocellular carcinoma; ICC, intrahepatic cholangiocarcinoma; PFS, progression-free survival.

The SOLACE study (NCT07141056/ChiCTR2400094830) is a multicenter prospective study designed to enroll approximately 700 patients across three cohorts: first-line immunotherapy for unresectable HCC, adjuvant immunotherapy after surgery, and neoadjuvant or conversion immunotherapy.^86,87 Anxiety and depression are assessed longitudinally using the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), 17-item Hamilton Depression Rating Scale (HAMD-17), and Hamilton Anxiety Rating Scale (HAMA), together with repeated measurements of stress hormones, inflammatory mediators, and immune-cell profiles. Associations will be examined with PFS, disease-free survival (DFS), and pathological response, respectively. The study spans distinct treatment stages and attempts to connect psychological phenotypes with neuroendocrine and immune markers. Its observational design, however, cannot fully eliminate reverse causation from tumor burden, treatment response, or physical symptoms.

Another multicenter study, NCT07325565, plans to enroll 651 patients with hepatobiliary malignancies, including cohorts with advanced HCC, high-risk resected HCC, and intrahepatic cholangiocarcinoma.⁸⁸ It will examine anxiety, depression, sleep, and quality of life in relation to immunotherapy outcomes, disease progression, and postoperative recurrence. The inclusion of caregiver psychological status broadens the analysis to the patient-family psychosocial environment, but heterogeneity across cancer types and treatment settings may complicate interpretation.

NCT07436845 focuses on patients with Barcelona Clinic Liver Cancer stage B or C HCC.⁸⁹ Ninety patients receiving HAIC combined with targeted therapy and immunotherapy are expected to undergo repeated PHQ-9 and GAD-7 assessments together with peripheral neuroendocrine and immune profiling. The primary endpoint is PFS, with objective response rate, disease control rate, overall survival, and safety as secondary endpoints. The study is particularly relevant to interventional oncology and may clarify whether psychological stress is associated with response to multimodal therapy. Its small sample and the effects of the treatment itself on psychological status and circulating biomarkers remain important limitations.

Among interventional studies, the HARMONY trial (NCT06541990) is a randomized pilot study of individualized psychoeducation and structured support for patients within 6 months of an HCC diagnosis, with feasibility, acceptability, psychological distress, and quality of life as the main outcomes.⁹⁰ NCT05942560 is designed to compare group cognitive behavioral therapy with health education in patients with liver cancer and anxiety or depression, assessing psychological symptoms, quality of life, immune function, and longer-term survival.⁹¹ The population is not restricted to HCC, however, and the implementation status requires continued monitoring. The PRIME-HCC trial (NCT06938945) uses an electronic patient-reported outcome platform to monitor symptoms and psychological status in patients receiving immunotherapy for HCC.⁹² Its primary purpose is to improve symptom management, quality of life, and healthcare utilization rather than to test a direct antitumor effect of psychological intervention.

Collectively, these ongoing studies integrate longitudinal psychological assessment, treatment outcomes, and selected neuroendocrine and immune measures. However, observational prospective protocols such as SOLACE, NCT07325565, and NCT07436845 do not include randomized psychological intervention arms. They can identify temporal associations between psychological stress, biomarkers, and oncologic outcomes, but cannot determine whether reducing stress changes the proposed biological pathways or improves treatment response, recurrence, or survival. Residual confounding and reverse causation will remain possible even when stress levels are associated with subsequent outcomes. These studies therefore cannot verify the complete causal pathway from stress reduction to biological change and improved oncologic outcomes. Nor have HCC trials directly targeted emerging mechanisms such as ADRB2-QPRT signaling, IPA deficiency, or taurocholate-related metabolic reprogramming.

Practical Applications for HCC Management

A practical application of the available evidence is the incorporation of repeated psychological screening into multidisciplinary HCC management. Assessment may be particularly relevant at diagnosis, before major treatment, during repeated locoregional or systemic therapy, at the first response evaluation, and when recurrence or disease progression is identified. Brief validated instruments for anxiety, depression, and psychological distress can be used as initial screening tools, but positive results should prompt clinical assessment rather than be interpreted in isolation. Fatigue, sleep disturbance, appetite loss, impaired concentration, and psychomotor changes may also reflect cirrhosis, hepatic encephalopathy, pain, treatment toxicity, or disease progression. Psychological findings should therefore be interpreted together with liver function, cognitive status, symptom burden, treatment exposure, and social circumstances. Patients with clinically significant symptoms may benefit from referral to psycho-oncology, psychiatry, palliative care, or structured behavioral-support services.^93,94

Psychological assessment may also inform supportive management around specific HCC treatments. Before liver resection or ablation, identifying severe anxiety, depression, poor sleep, and limited social support may enable earlier intervention and improve treatment preparation and postoperative recovery. During repeated transarterial chemoembolization, hepatic arterial infusion chemotherapy, or systemic therapy, psychological support may assist with pain management, anticipatory anxiety, treatment adherence, and continuity of care.⁹⁵ These applications may improve patient-reported outcomes and treatment engagement, but current evidence does not show that psychological screening or intervention should determine eligibility for locoregional therapy, alter the choice or intensity of anticancer treatment, or change surveillance schedules. Stress-related hormones, heart rate variability, inflammatory markers, and metabolic biomarkers should likewise remain research tools until their incremental clinical value and reproducibility have been established.

Challenges and Future Directions

Is Psychological Stress a Cause or a Consequence?

The relationship between psychological stress and HCC prognosis is bidirectional. Persistent anxiety, depression, or high stress may influence the disease course, whereas recurrence, deterioration in liver function, and worsening symptoms can in turn reshape psychological status. Longitudinal evidence shows that HCC recurrence is an important driver of declining postoperative quality of life, illustrating why an association between a single baseline psychological score and survival cannot be assumed to represent a causal effect.⁹⁶

Establishing temporal order is therefore essential. Future cohorts should assess psychological status before treatment and repeat measurements after treatment, at the first response assessment, at recurrence, and when treatment is changed, treating psychological status as a time-varying exposure rather than a fixed baseline characteristic. Analyses should determine whether psychological changes precede clinical events and should rigorously account for tumor stage, liver function, pain, sleep, sarcopenia, social support, and treatment exposure, rather than focusing narrowly on whether a single hazard ratio reaches statistical significance in a multivariable model.

HCC also differs from many cancers in that tumor-related and liver-related deaths coexist. Future studies should separately evaluate tumor recurrence, disease progression, hepatic decompensation, infection, bleeding, and cancer-specific mortality. Competing-risk or multistate models will be needed to determine whether psychological stress primarily affects tumor biology, hepatic vulnerability, or broader patterns of healthcare behavior.⁹⁷

Which Patients Have a Biologically Meaningful Stress Phenotype?

Patients with similar scores on psychological scales may not share the same biological stress state. Some may have sustained sympathetic hyperarousal, others may be characterized mainly by depression, social isolation, or circadian disruption, and still others may score highly because of pain, fatigue, or impaired liver function. Studies in other cancers have identified trajectories of persistently low stress, transient elevation followed by recovery, persistently high stress, and delayed escalation, suggesting that a single screening assessment may miss patients with poor resilience while misclassifying those with prominent somatic symptoms.^98,99

Future studies should characterize anxiety, depression, perceived stress, social isolation, fear of progression, and sleep disturbance separately and incorporate duration, rate of change, and temporal coupling with treatment milestones into risk stratification. The translational goal should not be a universal psychological cutoff, but the identification of stress endotypes defined by persistent psychological stress together with corresponding neuroendocrine or immunometabolic abnormalities.

Electronic patient-reported outcomes, wearable devices, and ecological momentary assessment can improve the temporal resolution of dynamic phenotyping.^100–102 The recruiting PRIME-HCC trial uses a WeChat-based platform to obtain weekly electronic symptom reports for 18 weeks from patients receiving immunotherapy, with threshold-triggered self-management advice and clinical alerts. Its principal objectives are to improve health-related quality of life and test the feasibility of digital monitoring rather than to intervene specifically on psychological stress or validate stress-related immune mechanisms.^92,103 Digital tools are therefore best viewed as infrastructure for capturing psychological and symptom trajectories and should be combined with standardized psychological assessment, clinical interviews, and biospecimen collection. Sleep, activity, and heart rate variability are also influenced by cirrhosis-related autonomic dysfunction and physical performance and must be interpreted alongside psychological measures and clinical events.

Do Peripheral Stress Markers Reflect Intratumoral Biology?

A central challenge in translating psychological stress into an oncologic variable is that peripheral measures may not represent intratumoral biology. Lower heart rate variability has been associated with poorer survival in HCC, but cirrhosis itself causes autonomic dysfunction. Cortisol and catecholamine concentrations are also influenced by sampling time, medications, pain, and acute hospitalization.^104,105 No single peripheral measure should therefore be treated as a specific surrogate for psychological stress.

Future studies should collect psychological scales, hair or salivary cortisol, heart rate variability, catecholamines, inflammatory mediators, and immune-cell phenotypes at the same time points and use repeated measurements to determine whether these markers change in parallel with psychological status. The joint association of anxiety scores and serum catecholamines with HCC recurrence and survival provides an initial rationale for such multimodal assessment, but independent validation is required.³⁴

More importantly, peripheral signals must be linked to tumor-tissue biology. QPRT expression, kynurenic acid/NAD+, IPA, and taurocholate are plausible candidate markers, but their clinical value depends on whether they correspond to intratumoral CD8+ T-cell function, endothelial-macrophage communication, or ferroptosis resistance.^40,42,43 Longitudinal, paired collection of blood, stool, and tumor tissue, coupled with spatial omics and mediation analysis, will be required to show that peripheral stress markers reflect rather than merely accompany intratumoral change.

Can Reducing Psychological Stress Alter Tumor Outcomes?

Psychological interventions in HCC have been shown to reduce anxiety and depression and improve sleep and quality of life, but whether reducing psychological stress lowers recurrence or prolongs survival remains unknown. A meta-analysis across cancer types suggested a small survival benefit from psychosocial intervention, but the prediction interval included no effect, indicating that benefit is highly dependent on cancer type, disease stage, and intervention format.⁷⁹ Future trials should use multicenter randomized designs with attention-matched active controls and include patient-reported, mechanistic, and clinical outcomes. Patient-reported outcomes should include anxiety, depression, sleep, pain, and quality of life; mechanistic outcomes should include cortisol rhythms, heart rate variability, immune-cell phenotypes, and metabolites; and clinical outcomes should distinguish treatment adherence, hepatic decompensation, tumor response, recurrence, and survival.

Existing registered studies also identify specific gaps in the next generation of trial design. SOLACE, NCT07325565,⁸⁸ and NCT07436845⁸⁹ can prospectively examine emotional stress in relation to immunotherapy or combined interventional treatment outcomes. None includes a randomized psychological intervention. HARMONY, NCT05942560,⁹¹ and PRIME-HCC evaluate psychological support, cognitive behavioral therapy, or dynamic symptom management. Their limitations include small samples, mixed cancer populations, uncertain recruitment status, and insufficient mechanistic assessment. Future mechanism-based trials should enroll patients with HCC who have persistent high stress and demonstrable neuroendocrine or immunometabolic abnormalities. A structured psychological intervention should be randomized alongside standard anticancer treatment. The trials should prespecify hierarchical endpoints for psychological symptoms, stress biomarkers, liver-related events, and oncologic outcomes. They should also include mediation analyses. Psychological care can be considered a disease-modifying strategy only if intervention-induced biological changes mediate the relationship between psychological improvement and tumor outcomes.

Conclusions, Implications of the Study, and Directions for Future Research

Psychological stress is emerging as a potential modifier of HCC through coordinated effects on neuroendocrine signaling, hepatic homeostasis, antitumor immunity, and metabolism.^106,107 However, current clinical evidence remains insufficient to establish causality, independent prognostic value, or a disease-modifying benefit from stress reduction. In current practice, repeated psychological screening and appropriate supportive intervention may improve psychological symptoms, treatment preparation, quality of life, and adherence, but psychological status should not yet be used to select or modify anticancer treatment. Future multicenter studies should combine longitudinal psychological assessment with matched blood, stool, and tumor samples to determine whether peripheral stress markers reflect intratumoral changes. Randomized trials should further examine whether psychological interventions produce measurable biological changes and whether these changes translate into improved liver-related and oncologic outcomes. Such evidence is required before psychological stress can be incorporated into precision risk stratification or disease-modifying treatment strategies for HCC.

Funding Statement

There is no funding to report.

Ethics Declarations

This review summarizes previously published studies and did not involve new human participants, animals, or patient-identifiable data.

Disclosure

All authors declare that they have no competing interests.