Reprogramming NF-κB signaling in cervical cancer: Implications for immune microenvironment and therapeutic resistance

Cervical cancer arises in a background of persistent human papillomavirus infection and chronic inflammation, yet therapeutic resistance and immune escape frequently occur in the absence of new genetic alterations. This highlights the importance of non-genetic, adaptive signaling mechanisms that enable tumor persistence. Among these, nuclear factor-κB (NF-κB) has emerged as a central regulatory node linking inflammatory stress, immune remodeling, and therapy tolerance. Rather than functioning as a binary inflammatory switch, NF-κB signaling in cervical cancer undergoes dynamic reprogramming, whereby distinct upstream stimuli selectively bias its transcriptional outputs toward immune checkpoint expression, myeloid recruitment, angiogenesis, tumor cell plasticity, and resistance to cytotoxic therapy. In this review, we synthesize recent mechanistic and translational studies to illustrate how NF-κB reprogramming reshapes the tumor immune microenvironment and drives therapeutic failure in cervical cancer. We highlight convergent NF-κB-dependent modules, including the PD-L1 immune checkpoint axis, inflammatory cytokine and chemokine networks, angiogenic remodeling, and anti-apoptotic survival programs. We further discuss the context-dependent duality of NF-κB signaling across tumor and immune compartments, the temporal evolution of NF-κB output states under therapeutic pressure, and emerging biomarker strategies to operationalize NF-κB dysregulation in the clinic. Finally, we outline rational approaches for precision modulation of NF-κB signaling, emphasizing modular and combination strategies over global pathway inhibition. Together, this framework positions NF-κB reprogramming as a unifying mechanism of immune evasion and therapeutic resistance, and as a targetable adaptive vulnerability in cervical cancer.