Post-Translational Governance of NF-κB in Cancer Immunity: Mechanisms and Therapeutic Horizons

Yue Hong^1,2Qian Long^1,2Ying Fu^3,4*

• ¹Department of General Surgery, The Second Xiangya Hospital, Central South University, No. 139, Renmin Central Road, Changsha 410011, China, Changsha, China
• ²Clinical Research Centre For Breast Disease In Hunan Province, No. 139, Renmin Central Road, Changsha 410011, China, Changsha, China
• ³Central South University, Changsha, China
• ⁴Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, Institute of Nephrology, The Second Xiangya Hospital at Central South University, Changsha, China, Changsha, China

Nuclear factor-κB (NF-κB) is a central transcriptional orchestrator of inflammation, immune modulation, and tumor progression. Beyond canonical signal transduction, the immunological functions of NF-κB are intricately governed by a spectrum of post-translational modifications (PTMs)-including phosphorylation, acetylation, ubiquitination, and methylation-that finetune its activation, nuclear translocation, DNA binding, and transcriptional specificity. In this Review, we explore how these context-dependent PTMs dynamically shape NF-κB's role in cancer immunity: promoting macrophage polarization, controlling antigen presentation by dendritic cells, regulating T cell exhaustion, and sustaining immunosuppressive networks within the tumor microenvironment. We further delineate how PTM-mediated NF-κB signaling interfaces with immune checkpoint expression-particularly PD-L1 and IDO1-and fuels resistance to immunotherapies. Emerging pharmacological strategies targeting NF-κBmodifying enzymes or degradation via PROTACs hold promise to reprogram the immune landscape. By integrating mechanistic insight with translational potential, we position NF-κB's post-translational regulation as a fertile axis for next-generation immunotherapeutic innovation.