During my PhD, I have been interested in the role of the innate immune receptor NLRP3, a key component of the inflammasome, in lung cancer development. Our results show the presence of a functional NLRP3 inflammasome in normal human bronchial epithelial cells (HBEC). Surprisingly, NLRP3 expression is strongly down-regulated in a large panel of NSCLC cell lines and patient tumors compared to healthy tissue. Moreover, we unravel that NLRP3 contributes to the transcription of H2AFX, the coding gene for the histone variant H2AX, in an inflammasome independent-manner. The deletion of NLRP3 in HBEC impairs double strand break signal amplification and transduction, resulting in a decrease in DNA repair. This repair defect leads to genomic instability, which is increased in lung adenocarcinomas expressing low levels of NLRP3. My PhD work identifies NLRP3 as a key factor of the DNA damage response and genomic integrity maintenance by regulating the transcription of H2AFX. This new role for NLRP3, together with its loss in NSCLC, makes it as a potential tumor suppressor