Background: Liver cancer represents a major global health burden, and targeted therapy combined with immune checkpoint inhibitors (ICIs) has become an essential systemic treatment. However, treatment-related symptom clusters may markedly impair quality of life (QOL). This study aimed to examine the longitudinal evolution of symptom clusters and their impact on QOL in patients with malignant liver tumors across the first to fourth treatment phases.

Methods: A prospective cohort of 150 patients receiving combined targeted-ICI therapy was recruited at a tertiary hospital in Qingyuan, China, between January and August 2025. The Chinese version of the Memorial Symptom Assessment Scale (MSAS-C) and the Quality of Life–Liver Cancer (QOL-LC) V2.0 questionnaire were distributed and collected on Day 7 of each treatment phase. The symptom-onset timeline was provided to patients at the initiation of therapy and retrieved on Day 7 of the first phase. Factor analysis, Apriori association rule mining, repeated-measures analysis of variance (ANOVA), correlation analysis, and stepwise multiple regression were applied to identify the dynamic structure of symptom clusters and their associations with QOL outcomes.

Results: The final cohort comprised 150 patients with a mean age of 53.62 years; 67.33% were diagnosed with hepatocellular carcinoma (HCC), and most were in advanced stages. Symptom burden increased progressively during treatment, with high-frequency symptoms, such as fatigue, dry mouth, weight loss, and sleep disturbance, affecting more than 70% of patients by Phase 4. Factor analysis identified 5, 4, 4, and 5 significant symptom clusters at T1–T4, respectively, while Apriori analysis further revealed key antecedent symptoms such as nausea, pain, and nervousness. All five symptom clusters demonstrated significant increases in severity over time (p < 0.001), especially those involving emotional-psychological and gastrointestinal symptoms. QOL scores declined markedly during Phases 3 and 4, with significant impairments in physical, psychological, and social functioning (all p < 0.01), and an overall score reduction exceeding 20 points (p < 0.001). Self-reported evaluations also revealed a substantial decline. The symptom clusters exhibited moderate to strong negative correlations with QOL, with the psychiatric symptom cluster showing a progressively stronger negative association with overall QOL scores from T1 to T4 (r = –0.51 to –0.64). Regression analyses identified psychiatric and emotional–psychological clusters as the strongest predictors of reduced QOL across all treatment stages (p < 0.001). In later phases, liver function-metabolic and gastrointestinal clusters also emerged as significant contributors. Demographic variables, including gender and treatment phase, exerted additional effects. The regression model demonstrated a good fit and stable residuals.

Conclusions: Combined targeted-ICI therapy is associated with a progressive increase in symptom cluster burden among patients with liver cancer, leading to a significant decline in QOL. Emotional and psychological symptom clusters exert the most persistent and profound effects, while liver function–metabolic and gastrointestinal symptom clusters become increasingly prominent in later stages.