Dual Role of Necroptosis in Cervical Cancer: Promoting Tumor Aggression and Modulating the Immune Microenvironment via the JAK2-STAT3 Pathway

Abstract Objective In the dynamic landscape of cervical cancer (CC) pathophysiology, this study aimed to elucidate the role of necroptosis in modulating tumor proliferation, invasion, and the immune microenvironment in CC. Methods In this study, the impact of necroptosis on CC was evaluated through a series of bioinformatical analyses and experimental approaches. The impact of necroptosis on CC was illustrated by analyzing its effects on tumor aggression, immune responses, and the JAK2-STAT3 signaling pathway. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), was also evaluated for its potential induction of necroptosis in CC cells and its interaction with necroptosis inhibitors. Additionally, the study assessed the influence of necroptosis on the immune microenvironment, particularly in T-cell-related pathways and the expression of tumor suppressor genes in CC. Results Necroptosis was found to enhance VEGFA expression through activation of the JAK2-STAT3 pathway, promoting tumor proliferative and invasive capabilities in CC. Bevacizumab induced necroptosis in CC cells, potentially leading to resistance in therapy. The combination of bevacizumab with necroptosis inhibitors attenuated VEGFA expression, suggesting a novel therapeutic strategy. Additionally, necroptosis activated T-cell-related pathways and promoted the infiltration and activation of Jurkat T cells. CD3D—a tumor suppressor gene in CC—was identified as a critical marker and its expression could be upregulated by necroptosis via the JAK2-STAT3 pathway in Jurkat T cells. Treatment of CC cells with supernatants from necroptosis-induced Jurkat cells resulted in reduced tumor cell proliferation and invasion. Conclusions This study reveals a complex interaction between necroptosis, tumor progression, and the immune response in CC. The findings propose a nuanced approach to leveraging necroptosis for therapeutic interventions, highlighting the potential of combining necroptosis inhibitors with existing therapies to improve treatment outcomes in CC.