Unveiling personalised targets of PD-1 blockade hyperprogression in a cervical adenocarcinoma via longitudinal single-cell and spatial monitoring

Cervical adenocarcinoma, a significant subtype of cervical cancer, exhibits variable responses to immune checkpoint inhibitors, with some patients experiencing hyperprogressive disease (HPD) characterised by accelerated tumour progression. The molecular and cellular mechanisms underlying HPD remain poorly understood. In this study, we employed single-cell RNA sequencing, T cell receptor profiling, and spatial transcriptomics to longitudinally analyse the tumour and its microenvironment of a single case of cervical adenocarcinoma who developed HPD following anti-PD-1 immunotherapy. Our integrated analyses revealed two key processes associated with HPD: Immunosuppression involving an IFNγ-STAT1-LAG3 axis in T cells, and fibroblast-supported epithelial proliferation and survival via IGF1-IGF1R signalling. Additionally, spatial transcriptomics identified the formation of a distinct pro-metastatic niche post-immunotherapy. These findings nominate LAG3 and IGF1R as candidate therapeutic targets in this patient and demonstrate the power of real-time, multi-modal profiling to identify adaptive hyperprogression mechanisms. Our work illustrates the potential value of longitudinal monitoring in precision oncology and provides a conceptual framework that could be tested for developing personalised interventions for minimal residual disease, non-responders, and HPD.