NLRP1 Shapes Immune and Inflammatory Signatures in Human Melanoma but Not in Mouse Models

Inflammasomes are multiprotein complexes that activate pro-caspase-1, leading to the maturation of the pro-inflammatory cytokines IL-1β and IL-18. Nlrp1 , the first receptor identified with inflammasome-forming capacity, is highly expressed in both the skin and immune cells. Despite its prominent role in these tissues, the function of Nlrp1 in melanoma remains poorly characterized. In this study, we investigated the impact of Nlrp1 on melanoma patient survival and found that its expression is associated with improved prognosis and with a co-expression network enriched for pro-inflammatory genes. However, in murine models, neither Nlrp1 expression nor activation significantly affected melanoma development or progression. Similarly, pharmacological activation of Nlrp1 using Val-Boro-Pro (VbP) did not alter tumor growth or the local inflammatory profile in mice but directly influenced CD25 ⁺ cell generation and glucose uptake in in vitro models. Finally, we demonstrated that a melanoma risk score can be constructed based on genes specific to inflammasome and pyroptosis pathways. Collectively, our findings reveal species-specific differences in NLRP1 function between humans and mice and support the potential of inflammasome-related pathways as prognostic biomarkers and therapeutic targets in human cancers.