Chemoradiation Reprograms Tumor Cells and the Immune Microenvironment in Cervical Cancer

Despite advances in screening and prevention, cervical cancer remains a leading cause of cancer-related deaths worldwide, underscoring the need for better treatments. In this study, we conducted a multicohort longitudinal study of human cervical tumors and the tumor microenvironment during chemoradiotherapy (CRT) and integrated RNA sequencing and single-cell transcriptomics to define the cellular and molecular programs shaping cell interactions and how CRT alters them. The analysis identified multiple therapeutic targets in CRT-resistant tumors, notably including MDM2, a key mediator of radiation responses in tumor and immune cells. MDM2 inhibition enhanced the effects of radiotherapy in human papillomavirus (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. The insights into therapy-induced changes in tumor and immune compartments could guide improved strategies against treatment-resistant HPV-positive cancers.