ArticleJournal for immunotherapy of cancer2026
Gasdermin D antagonizes immunosuppression in prostate cancer by inducing LAMC2 degradation to block M2 macrophage polarization.
Article in Journal for immunotherapy of cancer, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundThe N-terminal domain of gasdermin D (GSDMD) is a known suppressor of prostate cancer (PCa), primarily recognized for its tumoricidal pyroptotic function. However, research on the full-length GSDMD protein and its relationship with PCa remains unexplored. Therefore, the aim of this study was to investigate the potential non-pyroptotic mechanism of action of GSDMD in preventing PCa immune evasion.
methodsThe study used GSDMD deletion models to assess its impact on tumor progression and immune cell profiles. Molecular techniques, including protein interaction analysis, were employed to identify the binding partner of GSDMD and the subsequent signaling pathways. Correlative analysis was performed between GSDMD expression and immune markers in human PCa samples.
resultsGSDMD deletion increased tumor progression and reduced survival, cytotoxic T lymphocyte (CTL) activation/infiltration and tumor cell susceptibility to T-cell death, promoting an immunosuppressive tumor microenvironment (TME). GSDMD-bound laminin subunit gamma-2 (LAMC2), thus inducing its ubiquitin-mediated degradation. Consequently, GSDMD deficiency stabilized LAMC2, driving M2 macrophage polarization and CXC motif chemokine ligand 5 (CXCL5) secretion. CXCL5 interacted with CXCR2 to activate the AKT/NF-κB axis, increasing vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) and suppressing CTL activity. GSDMD expression in human PCa positively correlated with CD8
conclusionThis study reveals a novel non-pyroptotic pathway through which GSDMD inhibits PCa immune evasion by targeting LAMC2 for degradation, thereby preventing the establishment of an immunosuppressive TME. The findings suggest that activating GSDMD represents a promising therapeutic strategy to reprogram the TME from immunosuppressive ("cold") to immunoreactive ("hot"), potentially enhancing the efficacy of immunotherapy in advanced PCa.
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