Frontiers in immunology · 2026
Mapping the physical topology of the tumor immune microenvironment: macroscopic image fractals as surrogate markers for immune exclusion phenotype and treatment resistance in colorectal cancer liver metastases.
СтатьяНаблюдательное исследованиеМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Ziyi Guo, Zhou Wentao, Zou Kailin
Аннотация
BACKGROUND: The spatial tumor immune microenvironment (TIME) determines therapy response in colorectal cancer liver metastases (CRLM). To overcome biopsy sampling bias, this study investigates multimodal macroscopic image fractal dynamics to non-invasively map immune physical barriers and metabolic states, constructing a multi-scale immune-radiomics joint score (IRJS) for robust prognostic stratification and exploratory assessment of treatment resistance.
MATERIALS AND METHODS: This dual-center observational study enrolled 270 CRLM patients with dual-modality imaging (contrast-enhanced magnetic resonance imaging, CE-MRI, 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed-tomography, 18F-FDG PET/CT) and digital spatial pathology. Patients were spatiotemporally divided into training (n=150), prospective temporal validation (n=45), and external validation (n=75) cohorts. Structural (FD_MRI) and metabolic (FD_PET) fractal dimensions were combined with the systemic immune-inflammation index (SII) and KRAS status to build the IRJS using XGBoost, utilizing the SHAP framework to evaluate mapping mechanisms.
RESULTS: FD_MRI positively correlated with α-SMA+ pro-fibrotic stromal density (r = 0.684), which may reflect the mechanical barrier excluding CD8+ T cells. FD_PET showed a significant association with core hypoxia (HIF-1α) and systemic immune exhaustion. IRJS robustly identified the immune-inflamed phenotype across training, temporal, and external validation cohorts (AUCs: 0.921, 0.886, 0.862, respectively). The IRJS-identified inflamed phenotype was an independent protective factor for overall survival (HR = 0.31, P < 0.001). Furthermore, IRJS demonstrated significant clinical net reclassification improvement (NRI = 0.384, P < 0.001) and net clinical benefit in decision curve analysis.
CONCLUSION: Dual-modal fractal dynamics provide non-invasive surrogate markers for mechanical constraints and metabolic exhaustion in CRLM. The IRJS model enables robust spatiotemporal assessment of immune evasion, offering multidisciplinary teams a potential framework to explore non-invasive biopsy decisions, prognostic stratification, and provide exploratory insights into potential immunotherapy resistance.
MATERIALS AND METHODS: This dual-center observational study enrolled 270 CRLM patients with dual-modality imaging (contrast-enhanced magnetic resonance imaging, CE-MRI, 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed-tomography, 18F-FDG PET/CT) and digital spatial pathology. Patients were spatiotemporally divided into training (n=150), prospective temporal validation (n=45), and external validation (n=75) cohorts. Structural (FD_MRI) and metabolic (FD_PET) fractal dimensions were combined with the systemic immune-inflammation index (SII) and KRAS status to build the IRJS using XGBoost, utilizing the SHAP framework to evaluate mapping mechanisms.
RESULTS: FD_MRI positively correlated with α-SMA+ pro-fibrotic stromal density (r = 0.684), which may reflect the mechanical barrier excluding CD8+ T cells. FD_PET showed a significant association with core hypoxia (HIF-1α) and systemic immune exhaustion. IRJS robustly identified the immune-inflamed phenotype across training, temporal, and external validation cohorts (AUCs: 0.921, 0.886, 0.862, respectively). The IRJS-identified inflamed phenotype was an independent protective factor for overall survival (HR = 0.31, P < 0.001). Furthermore, IRJS demonstrated significant clinical net reclassification improvement (NRI = 0.384, P < 0.001) and net clinical benefit in decision curve analysis.
CONCLUSION: Dual-modal fractal dynamics provide non-invasive surrogate markers for mechanical constraints and metabolic exhaustion in CRLM. The IRJS model enables robust spatiotemporal assessment of immune evasion, offering multidisciplinary teams a potential framework to explore non-invasive biopsy decisions, prognostic stratification, and provide exploratory insights into potential immunotherapy resistance.