Stimulator of interferon genes-targeted positron emission tomography tracks early microbiota-induced tumor immune remodeling and guides immunotherapy

Immune checkpoint inhibitors (ICIs) have made dramatic evolution in cancer management, yet their curative effect remains limited in most tumors characterized by "cold" immunophenotype. Immune remodeling by transforming "cold" tumor to "hot" one is essential to improve ICIs response, and gut microbiota modulation has emerged as a promising approach. Nevertheless, a significant challenge lies in the absence of reliable tools for early assessment of immune remodeling. To address this, we focused on the stimulator of interferon genes (STING), an essential molecule for launching anti-tumor immunity, and developed the STING-targeted PET tracer [¹⁸F]FBTA. [¹⁸F]FBTA-PET detected a significant increase in tumor uptake with a more homogeneous spatial distribution following Lactobacillus rhamnosus GG (LGG) treatment. This increased [¹⁸F]FBTA tumor uptake was prior to changes in tumor volume, T cell infiltration, and [¹⁸F]FDG-PET signals, and showed a strong correlation with STING expression in tumor tissues. The immune remodeling mediated by LGG administration, as captured by [¹⁸F]FBTA-PET, was also successfully replicated in recipient mice through fecal microbiota transplantation. Guided by [¹⁸F]FBTA-PET, the combination of LGG with αPD-L1 achieved superior anti-tumor efficacy. Furthermore, [¹⁸F]FBTA binding radioactivity positively correlated with STING expression in patients' tumor tissues. Our results established [¹⁸F]FBTA-PET as a robust indicator for early assessment of immune remodeling and guiding ICI-based combination therapies, highlighting its potential for clinical translation.