A Multi-stage Precision Stratification (MPS) Framework for Navigating Adjuvant Immunotherapy in Hepatocellular Carcinoma After Resection
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
Recurrence rates following curative resection for hepatocellular carcinoma (HCC) remain persistently high, benefit from adjuvant immunotherapy varies substantially across patients, and the field currently lacks a standardized framework to characterize the postoperative host immune contexture.
Purpose
To propose and validate a Multi-stage Precision Stratification (MPS) framework and evaluate its value in prognostic stratification and prediction of immunotherapy response.
Methods
The Immune Health Index (IHI = S + R − E) integrating immune surveillance (S), immune exhaustion (E), and immune reserve (R) was constructed to define four immune phenotypes. Prognostic value was assessed in four public HCC cohorts (n=931) with single-cell transcriptomic validation (GSE140228, 61,690 cells); a blood-count-based clinical version cIHI_v8 was constructed in the Qinghai QPHCC cohort (n=490 survival analysis).
Results
IHI was an independent protective prognostic factor in TCGA-LIHC (multivariate HR=0.795, P=0.034); four-cohort random-effects meta-analysis yielded HR=0.818 (95% CI: 0.696–0.961), I²=31.4%. QPHCC cIHI_v8 multivariate HR=0.452, HR=0.715 after ALBI adjustment; Bayesian evidence synthesis yielded BF_10=1280 for cIHI_v8 (>100 constitutes Decisive evidence), whereas the 4-cohort meta BF_10=2.19 (Anecdotal). Following NLP-based reverse stage derivation (n=490, achieving full AJCC/BCLC stage coverage from 0%), IHI remained significant after AJCC adjustment (HR=0.8642, P=0.000079), IHI provided positive incremental C-index across all stage-adjusted models; stratified analysis showed the strongest effect in early-stage (AJCC I-II: HR=0.8109, P<0.0001) and MVI-negative patients (HR=0.8538, P=0.0020). Bootstrap 1000× resampling: median HR=0.8646 (95% CI: 0.7985–0.9443), all iterations yielded HR<1.
Conclusions
The MPS framework provides a mechanism-driven biological stratification tool for adjuvant immunotherapy in post-resection HCC, moving from “fixed-protocol extrapolation” to “immune contexture navigation.”
