MUST-PET: MUltimodal Self-supervised learning across Tracers for whole-body PET/CT-based lesion segmentation

Deep learning-based whole-body PET-CT lesion segmentation can support cancer staging, treatment planning, and response assessment, but generalization is limited by scarce annotations and domain shifts. Self-supervised learning (SSL) can address these challenges but remains underexplored in pan-cancer, multi-tracer PET-CT. In this work, we propose MUST-PET (MUltimodal Self-Supervised learning across Tracers), a multimodal, multi-tracer SSL framework for generalizable whole-body PET-CT lesion segmentation. MUST-PET is trained and validated on a diverse, multi-institutional collection of pan-cancer PET-CT scans acquired with FDG and prostate-specific membrane antigen (PSMA)-targeted radiotracers. MUST-PET uses context-aware masked reconstruction, where one modality is partially masked and reconstructed using complementary information from both PET and CT. The pretrained model is subsequently fine-tuned with labeled samples and evaluated for reconstruction quality, lesion segmentation, label efficiency, and generalizability across independent held-out datasets. MUST-PET reduces reconstruction error, improves lesion segmentation over training from scratch, and performs well with limited labeled data and on unseen external datasets, demonstrating the potential of multi-tracer SSL for label-efficient, generalizable whole-body PET-CT. segmentation.