Celebrating the 40-year milestone: NF-ĸB in oncoimmunity

Since its discovery by Dr. David Baltimore nearly 40 years ago, and in light of his recent passing, NF-κB has once again come into sharp focus as a central regulator of diverse cellular processes, including immune responses, inflammation, and cell survival. Its dysregulation is implicated in a wide range of human diseases, with mounting evidence highlighting its pivotal role in cancer and oncoimmunity. This review provides an integrated overview of NF-κB family members and their canonical and noncanonical signaling pathways, emphasizing how context-dependent activation orchestrates complex cellular outcomes. Within the tumor microenvironment (TME), NF-κB regulates crosstalk among cancer cells, immune subsets, and stromal components, promoting proliferation, metastasis, and immune evasion. We summarize FDA-approved and orphan-designated drugs targeting NF-κB, along with emerging therapeutics in clinical and preclinical development. Innovative strategies, including tumor-targeted delivery, immune checkpoint combination, nanocatalytic, and epigenetic modulation, are redefining NF-κB-directed therapy. Looking ahead, future efforts should focus on understanding context-specific NF-κB signaling, optimizing combination therapies, improving drug delivery and bioavailability, and identifying predictive biomarkers for patient stratification. Moreover, the emerging integration of artificial intelligence holds promise to accelerate discovery and personalize NF-κB-targeted therapies. Collectively, FDA-approved agents, experimental compounds, and novel strategies underscore NF-κB modulation as a versatile and promising avenue for cancer and immune disease therapy.