In 2010 we published a provocative review entitled “Why not treat human cancer with interleukin-1 blockade?” and suggested that clinical trials using IL-1 blockade should be considered since the safety and the clear benefits observed blocking IL-1 activity in several animal models of tumorigenesis and metastasis (Dinarello, 2010). More than 10 years later, this proposal based on preclinical data is now taking place in human studies. For example, the importance of IL-1 in tumor development has been recently confirmed in a randomized, placebo controlled clinical trial of over 10,000 subjects with atherosclerosis treated with a monoclonal antibody against IL-1β (Ridker, Everett, et al., 2017). A sub-analysis of patients demonstrated a lower incidence of lung cancer and a reduced cumulative incidence of fatal cancers in this population (Ridker, MacFadyen, et al., 2017). These and other data reveal the role of inflammatory cytokines such as IL-1β in cancer progression.

The past two decades also identified an important step forward in the understanding of IL-1 and IL-1 Family members biology with the characterization of the Nucleotide-binding domain and Leucine-rich Repeat (NLR) family, a sub-group of the Pattern Recognition Receptors (PRRs) family (Inohara, McDonald, & Nunez, 2005). Several members of the NLR family assemble in multimolecular complexes termed inflammasomes. Inflammasomes are a major regulator of innate immune responses to both endogenous and exogenous stimuli mediating a potent inflammatory response. Specifically, NLRs convert the biologically inactive pro-IL-1β and pro-IL-18 into their active forms by the enzymatic activity of caspase-1 (Franchi, Eigenbrod, Munoz-Planillo, & Nunez, 2009). Although inflammasome function is critical for the host defense against infections, dysregulated NLRs activity leads to amplification of the inflammatory response and ultimately to tissue damage. In the context of tumorigenesis, several NLRs contribute to tumor progression by their ability to modulate the inflammatory response, creating a tumor permissive environment. Of the NLRs members, there is a particular interest on NLRP3. NLRP3 expression and activation is increased in several malignancies compared to the healthy matching tissue (Figure 1). This review summarizes the current knowledge on NLRP3 activation in cancer and the role of this NLR in cancer pathogenesis and progression.