Multimodal Imaging of Hypoxia, Metabolism and pH in Feline Sarcoma Using Hyperpolarized ¹³C MRI and PET

Direct in vivo characterization of the interplay between tumor hypoxia, acidosis, and metabolic reprogramming remains a major translational challenge. Here, we establish a clinically deployable simultaneous PET/MRI workflow on a clinical 3 T system that combines hyperpolarized ¹³C MRI of [1-¹³C]pyruvate to map metabolic flux, [1,5-¹³C₂,3,6,6,6-D₄]zymonic acid to probe extracellular pH, and [¹⁸F]FMISO PET to quantify hypoxia. Recruitment of domestic cats bearing sarcoma as a clinically relevant and comparative disease model yielded a highly heterogeneous study cohort. All modalities could be applied successfully and allow for simultaneous, coregistered mapping of acidification in spontaneous tumors in domestic cats for the first time, complemented by imaging of metabolism and hypoxia. Correlation of imaging parameters provides a multi-dimensional assessment of inter- and intratumoral heterogeneity, which indicates distinct parameter correlation fingerprints for different subtypes. This multiparametric protocol allows for new insights into the metabolic program of sarcoma, suggesting tumor acidification to be coupled with hypoxia and increased lactate production. Moreover, pH imaging shows strong potential for assessing sarcoma aggressiveness and related subject outcomes. Together, these results establish a translationally deployable, simultaneous PET/MRI workflow for integrated imaging of tumor metabolism and microenvironment, which supports efforts to translate pH imaging for patient stratification and therapy monitoring.