Nuclear factor NF-kappa-B p65 subunit–NACHT, LRR and PYD domains-containing protein 3 axis (NF-κB p65–NLRP3 axis)

The NF-κB p65–NLRP3 axis is a critical signaling cascade in tumor-associated macrophages (TAMs) that integrates inflammatory stimuli with the innate immune response. In this axis, the NF-κB subunit p65 (RELA) provides the essential "priming" signal by translocating to the nucleus and upregulating the transcription of the NLRP3 sensor and the pro-inflammatory cytokine pro-interleukin-1β [1, 3]. Upon a secondary activation signal, the NLRP3 protein oligomerizes to form an inflammasome complex, which activates Caspase-1 to process pro-cytokines into their mature forms (IL-1β and IL-18) and potentially trigger pyroptotic cell death [2, 3]. In the tumor microenvironment, dysregulation of this axis often promotes an immunosuppressive milieu that supports tumor growth, angiogenesis, and metastasis [3, 6]. Therapeutic strategies targeting this axis aim to modulate the inflammatory profile of TAMs, either by inhibiting chronic pro-tumorigenic inflammation or by re-polarizing macrophages toward an anti-tumor phenotype [4, 6]. Pharmacological intervention typically involves small-molecule inhibitors of NLRP3, such as MCC950 and Dapansutrile, or inhibitors of the NF-κB pathway to prevent the initial priming step [4, 5].

Other names

RELA-NLRP3 signaling pathwayNF-kappaB-NLRP3 axisp65-NLRP3 inflammasome axisNF-κB/NLRP3 signaling

Inhibition of NF-κB-mediated transcriptional priming of NLRP3 and pro-IL-1β, or direct blockade of NLRP3 inflammasome assembly and activation.