Chemoradiation Reprograms Tumor Cells and Immune Microenvironment In Cervical Cancer [scRNA-seq]

Despite advances in screening and prevention, cervical cancer remains a leading cause of cancer-related deaths worldwide, underscoring the need for better treatments. Here, we present a multi-cohort longitudinal study of human cervical tumors and the tumor microenvironment during chemoradiation therapy (CRT). Integrating RNA sequencing, single-cell transcriptomics, and in vivo validation, we define the cellular and molecular programs shaping cell interactions and document how CRT alters them. We identify multiple therapeutic targets in CRT-resistant tumors, notably MDM2, a key mediator of radiation responses in tumor and immune cells. MDM2 inhibition enhanced radiotherapy effects in HPV-positive, TP53 wild-type cervical cancer cells, improved radiation response and reshaped the immune landscape in preclinical models. These findings highlight the potential of combining MDM2 inhibition with CRT to overcome resistance and improve patient outcomes. Our data provides novel insights into therapy-induced changes in tumor and immune compartments, guiding new strategies against treatment-resistant HPV-positive cancers. Overall design: scRNA-seq of primary tumor samples from 10 cervical cancer patients treated with definitive chemoradiation obtained before treatment (pre-RT), and at 1–2 weeks (on-RT#1) and 2–3 weeks (on-RT#2) after the initiation of chemoradiation