Treatment-Stratified Immune–Inflammatory Trajectories and Early Response in Patients with Hepatocellular Carcinoma Receiving Systemic Therapy

Background: Systemic therapy outcomes in hepatocellular carcinoma (HCC) remain heterogeneous, and treatment selection is still largely guided by clinical eligibility rather than dynamic biologic response. We evaluated whether accessible standard-of-care immunophenotypic and immune–inflammatory markers, tumor-marker kinetics, and immune-context variables could generate treatment-stratified early response signals. Methods: We conducted a retrospective analysis of 153 unique patients with HCC, each contributing one systemic therapy episode. First on-treatment imaging response was classified as complete response, partial response, stable disease, or progressive disease. Routine immune-cell indices, including neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and systemic immune-inflammation index (SII), were evaluated at baseline and early post-treatment timepoints. Alpha-fetoprotein (AFP) kinetics and overall survival were analyzed descriptively. Results: A total of 153 patients were included: 124 received immunotherapy-based therapy and 29 received tyrosine kinase inhibitor (TKI) therapy. Overall objective response rate was 26.8%, disease control rate was 56.2%, and progression occurred in 43.8%. AFP trajectory separated responder from non-responder phenotypes, supporting the value of dynamic marker change. Treatment-stratified trajectories revealed distinct patterns: among immunotherapy-treated patients, Week 2 SII increase was associated with progression at first on-treatment imaging (median log2 ratio 0.17 vs. −0.24 for progression vs. non-progression; p = 0.026), whereas TKI response was associated with lymphocyte expansion and decline in neutrophil-dominant inflammatory indices. Conclusions: Routine immune–inflammatory trajectories, particularly early SII change, may provide clinically relevant treatment-stratified response signals in patients with HCC receiving systemic therapy. These findings support interpreting standard clinical markers as evolving biologic trajectories rather than isolated prognostic scores and provide a practical foundation for future biomarker-informed treatment strategies.