Necroptosis as a key player in cervical cancer progression and management: a systematic review and transcriptomic cross-study consensus analysis

Abstract

Immunotherapy has improved outcomes for a subset of patients with locally advanced cervical cancer. However, many tumors remain immunologically “cold” and fail to respond. Strategies that enhance tumor immunogenicity are therefore of increasing interest. Necroptosis, a regulated form of inflammatory cell death, has emerged as a potential mechanism capable of promoting the anti-tumor immune responses through the release of damage-associated molecular patterns and enhanced antigen presentation. In this study, we performed a systematic review and transcriptomic cross-study consensus analysis of all studies carried out describing the role and mechanisms of necroptosis occurrence in cervical cancers. We analyzed all published necroptosis-related prognostic gene signatures and integrated these findings into an exploratory transcriptomic analyses to identify mechanistic insights into interlinked biological pathways, and potential therapeutic targets. Following PRISMA guidelines, we analyzed seven published prognostic models, from studies using RNA sequencing and least absolute shrinkage and selection operator (LASSO)-based feature selection to generate a prognostic risk score for patients. We then conducted a comparative analyses of eight overlapping genes and their reported risk score coefficients. Across studies, seven necroptosis-related genes were identified, many of which are functionally linked to mitochondrial transport and permeability regulation, reactive oxygen species (ROS) generation, and inflammatory signaling. Overall, our findings support a key role for necroptosis in cervical cancer, where activation thereof is generally associated with enhanced immune infiltration and activation; thereby improved prognosis. These findings position necroptosis as a promising target for combination therapy strategies aimed at converting immunologically “cold” tumors into more responsive phenotypes. By integrating published signatures with exploratory analyses, we identify potential avenues to modulate necroptotic signaling in ways that may enhance synergy with immunotherapies, and have synthesized a hypothetical cell signaling and interaction diagram. Collectively, this work provides a foundation for future experimental validation and therapeutic development.