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.

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.