Tito A. Sandoval, Yize Li, Naoshad Muhammad, Tresha P. Desai, Reyka G. Jayasinghe, Saman Zeeshan, Kay Jayachandran, Matthew Inkman, Michael R. Waters, Eliwaza Naomi S. Msengi, Tyler McKinnish, Ibrahim Hatipoglu, Ana Carolina Paschoalini Mafra, Muyassar Anwar, Donghua Hu, Dhaval P. Bhatt, Varintra E. Lander, R. Jay Mashl, Andrew Houston, Liyun Chen, J. Contreras, Clifford G. Robinson, S. J. Davies, Julie Belmar, Shunqiang Li, Michael B. Major, David G. DeNardo, Stephanie Markovina, Brian T. Edelson, Jin Zhang, Li Ding, Julie K. Schwarz
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. SIGNIFICANCE: Mapping of the impact of chemoradiation on cellular interactions in cervical cancer reveals how treatment reshapes the tumor microenvironment and highlights targets for developing future immunotherapeutic approaches. See related commentary by Klopp, p. 1540.