Role of pyroptosis in melanoma: Molecular mechanisms and therapeutic potentials

Gasdermin family proteins function as executioner molecules in pyroptosis, a programmed necrotic pathway characterized by two sequential molecular events: the formation of supramolecular complexes known as inflammasomes, followed by proteolytic activation of specific cysteine-aspartic acid specific proteases. Subsequent to pore assembly, catastrophic permeabilization of the plasma membrane enables efflux of intracellular contents including canonical inflammatory cytokines (e.g., interleukin-18, interleukin-1β) and chemokines, generating a storm of inflammatory mediators that amplify immune responses. Originally, pyroptosis was considered merely as an innate immune defense mechanism against pathogenic infections. Emerging evidence now reveals that pyroptosis exhibits dual functionality through its capacity to reshape the tumor immune microenvironment. On the one hand, it releases tumor-associated antigens to promote the activation of antigen-presenting cells. On the other hand, the cytotoxicity and immunotherapeutic response rate of cytotoxic T cells are significantly enhanced by activation of the T cell receptor signaling pathway and cytokine network (e.g., interferon-γ, tumor necrosis factor-α). In melanoma, pyroptosis-related gene signatures are associated with prognosis and the tumor immune microenvironment, and they have been used to computationally predict responses to immune checkpoint inhibitors and some targeted agents; however, evidence for true therapeutic synergy with PD-1 or CTLA-4 blockade is largely preclinical and remains to be validated in clinical studies since so far there is no large, prospective, melanoma-specific trial demonstrating evidence for therapeutic synergy.