Survivin inhibition induces PD-L1 expression through cGAS stabilization and attenuates antitumor immunity
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Background
Survivin is a mitotic regulator frequently overexpressed in human cancers and an attractive therapeutic target. However, how Survivin inhibition influences tumor immune regulation remains incompletely understood. This study aimed to investigate whether Survivin inhibition modulates antitumor immunity and to elucidate the underlying mechanisms.
Methods
Programmed death-ligand 1 (PD-L1) expression was evaluated in multiple tumor cell lines following pharmacological or genetic inhibition of Survivin. Mechanistic studies included RNA sequencing, immunoblotting, flow cytometry, cGAS knockdown, and NF-κB inhibition. Immune profiling was performed using CD8⁺ T-cell cytotoxicity assays, mass cytometry, flow cytometry, immunofluorescence and single-cell RNA sequencing. Clinical relevance was assessed using patient tumor specimens and public immunotherapy cohorts.
Results
Survivin inhibition, either by YM155 treatment or genetic depletion, increased PD-L1 expression at both mRNA and protein levels in tumor cells. Mechanistically, Survivin inhibition stabilized cyclic GMP – AMP synthase (cGAS) by reducing its ubiquitination and activated NF-κB signaling, thereby promoting transcriptional upregulation of PD-L1. Functionally, the induced PD-L1 enhanced PD-1 engagement and suppressed CD8⁺ T-cell cytotoxicity, promoting immune evasion. In immunocompetent ovarian cancer models, pharmacological inhibition of Survivin increased PD-L1 expression in tumor and immune compartments and attenuated cytotoxic immune activity. PD-L1 blockade restored antitumor immunity and significantly enhanced the therapeutic efficacy of Survivin inhibition. In addition, analyses of patient samples and public single-cell datasets revealed an inverse association between Survivin and PD-L1 expression, and high Survivin expression was associated with reduced benefit from PD-1/PD-L1 blockade.
Conclusions
These findings identify a Survivin–cGAS–PD-L1 axis linking mitotic stress to immune suppression and provide a mechanistic rationale for combining Survivin-targeted therapy with immune checkpoint blockade.
