Peripheral blood CXCL1 serves as a non-invasive dynamic biomarker for intratumoral colonization of attenuated Salmonella.

Abstract

Attenuated oncolytic bacteria represent a promising targeted delivery platform for cancer therapy; however, the lack of non-invasive biomarkers to monitor their persistent intra-tumoral colonization severely limits clinical translation, efficacy assessment, and safety monitoring. Here, we identify the sustained elevation of peripheral blood CXCL1 as a dynamic, non-invasive biomarker for the persistent colonization of attenuated Salmonella in solid tumors. Across four orthotopic preclinical models (including lung, breast, and bladder cancers, as well as melanoma), effective bacterial colonization specifically drove prolonged systemic CXCL1 elevation. Focusing specifically on the melanoma model, rapid bacterial eradication via intratumoral antibiotics restored CXCL1 to baseline. Furthermore, comparisons with a colonization-deficient mutant strain confirmed that CXCL1 elevation strictly depends on intra-tumoral, rather than systemic, bacterial burden. Mechanistically, single-cell RNA sequencing (scRNA-seq) revealed that tumor-colonizing bacteria profoundly reshape the tumor microenvironment by directly activating and recruiting neutrophils, monocytes, and cancer-associated fibroblasts (CAFs), which act as the primary cellular sources of CXCL1 production and systemic leakage. These findings highlight peripheral blood CXCL1 as a robust and actionable biomarker for real-time monitoring of oncolytic bacterial colonization, providing crucial guidance for dosing optimization and biosafety evaluation in clinical applications.