An immunosuppression imaging gauge prospectively predicts metastatic progression and immunotherapy resistance in breast cancer

Abstract

Systemic immunosuppression promotes metastatic progression and immunotherapy resistance, yet reliable biomarkers and noninvasive tools for longitudinal monitoring remain limited. Building on our finding that CXCL1+ neutrophil abundance in major organs inversely correlates with breast cancer-induced systemic immunosuppression, we developed an imaging-based immunosuppression gauge using CXCR2-expressing cells that mimic CXCL1+ neutrophil trafficking. Following intravenous administration, the biodistribution of engineered CXCR2-overexpressing mesenchymal stem cells or healthy donor neutrophils was imaged at 24 h, with greater organ accumulation indicating lower systemic immunosuppression. These living, distributed biosensors integrate chemokine signals across multiple organs and convert host immune status into an imageable biodistribution pattern. The gauge distinguished tumor aggressiveness at early disease stages, predicted metastatic risk before overt metastatic outgrowth, identified chemoimmunotherapy responders, and informed treatment selection through longitudinal immune monitoring. Mechanistically, nonaggressive tumors failed to induce substantial systemic immunosuppression and were effectively controlled by surgery alone, whereas aggressive tumors continued to drive immunosuppression after resection. Neoadjuvant chemoimmunotherapy produced superior outcomes to adjuvant treatment by intervening before profound immunosuppression developed and more effectively restoring antitumor immunity. Across cancer models, long-term survivors consistently showed resolution of systemic immunosuppression and restoration of immune activity to healthy-host levels. Thus, imaging systemic immunosuppression provides an early, longitudinal indicator of metastatic risk, therapeutic response, and treatment efficacy.