Peripheral immune dynamics during treatment predict prognosis in HCC receiving TACE plus ICIs and anti-VEGF/TKIs

To evaluate the prognostic value of peripheral immune markers and their static and dynamic changes during different treatment stages in patients with hepatitis B virus (HBV)-related unresectable hepatocellula carcinoma (uHCC) receiving transarterial chemoembolisation (TACE) combined with immune checkpoint inhibitors (ICIs) and anti-vascular endothelial growth factor (anti-VEGF) antibodies or tyrosine kinase inhibitors (TKIs).

This single-centre retrospective study included patients with HBV-related uHCC treated with TACE combined with ICls and anti-VEGF antibodies or TKIs between July 2019 and July 2024. Peripheral blood immune indicators were collected at baseline (Cycle 0), the second treatment cycle (Cycle 2) and the fourth treatment cycle (Cycle 4). The primary outcome was overall survival (OS), while secondary outcomes included progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR), with tumour response assessed at the first treatment evaluation (at the end of the fourth treatment cycle) based on mRECIST criteria. Longitudinal changes between adjacent time points were calculated (Δ: Cycle 2 - Cycle 0; Δ2: Cycle 4 - Cycle 2). Both static values and dynamic changes in immune markers were subjected to LASSO-Cox and stepwise multivariate Cox regression analyses to identify independent predictors of OS. Based on the significant variables, a prognostic nomogram and an immune-based risk score model were developed. To further assess prognostic heterogeneity, patients were stratified by K-means clustering according to the temporal patterns of the most predictive immune marker, and survival outcomes were compared across the resulting subgroups.

A total of 67 HBV-related uHCC patients treated with TACE plus ICIs and anti-VEGF antibodies/TKIs were included. The cohort had a median follow-up of 18.2 months, with a median overall survival (mOS) of 30.4 months and a median progression-free survival (mPFS) of 11.0 months. At the first evaluation, the objective response rate (ORR) was 53.7%, and the disease control rate (DCR) was 86.6%. LASSO-Cox regression identified several static and dynamic immune markers associated with OS. Ultimately, CD4⁺/CD8⁺ ratio at Cycle 4 (HR = 0.58, p = 0.035), Δ2 NLR (HR = 1.66, p = 0.014), and Δ2 CD3⁺CD4⁺ (HR = 0.04, p = 0.007) were confirmed by stepwise multivariate Cox regression. A prognostic nomogram incorporating these variables demonstrated favourable predictive performance (C-index = 0.72; AUCs = 0.750, 0.722 and 0.854 for 1-, 2- and 3-year OS, respectively). The derived immune-based risk score effectively stratified patients into high- and low-risk groups with significantly different OS (11.5 vs. 34.0 months, p < 0.001) and PFS (7.5 vs. 13.8 months, p = 0.006). The risk score showed a positive correlation with Δ2 NLR (r = 0.50) and negative correlations with CD4⁺/CD8⁺ ratio (r = -0.64) and Δ2 CD3⁺CD4⁺ (r = -0.45). Based on CD3⁺CD4⁺ trajectory clustering, three distinct immune dynamic subtypes were identified, among which the continuous decline group exhibited the poorest prognosis (p = 0.042).

This study demonstrates the prognostic relevance of peripheral immune markers in patients with HBV-related uHCC receiving combination therapy. Immune dynamics observed during later treatment stages, rather than baseline measurements, were more strongly associated with overall survival. A risk model based on the CD4⁺/CD8⁺ ratio at Cycle 4, Δ2 NLR and Δ2 CD3⁺CD4⁺ enabled effective prognostic stratification and may provide a useful framework for risk assessment in this patient population.