Dexamethasone activates anti-tumor immunity in multiple myeloma by dismantling the GR-PPP1CB complex to restore STING/IRF3 signaling

Background: The Cyclic GMP-AMP Synthase/stimulator of interferon genes (cGAS-STING) pathway mediates anti-tumor immunity by sensing cytosolic DNA and producing type I interferons, but is frequently suppressed in multiple myeloma (MM), enabling immune evasion. Dexamethasone (DXM), a cornerstone glucocorticoid in MM therapy, is paradoxically combined with immunotherapies despite its immunosuppressive reputation. The mechanisms by which DXM and its Glucocorticoid Receptor (GR) modulate the MM immune microenvironment remain elusive.

Methods: We analyzed the tumor immune microenvironment using single-cell RNA Sequencing in 5TMM3VT murine models. STING-knockout mice were employed for genetic validation, and the PP1 inhibitor salubrinal for pharmacological studies. Protein-protein interactions were examined by co-immunoprecipitation, mass spectrometry, and immunofluorescence. NK cell cytotoxicity and macrophage polarization were assessed using co-culture systems with flow cytometry, quantitative Real-Time PCR, and ELISA.

Results: We identified that GR constitutively recruits the Phosphatase PPP1CB to dephosphorylate and inactivate the TBK1-IRF3 complex, thereby suppressing cGAS-STING signaling in MM cells under basal conditions. As the specific ligand of GR, DXM rapidly binds to GR, leading to the disruption of the GR-PPP1CB-TBK1-IRF3 complex, which in turn reactivates STING signaling and induces interferon-stimulated gene expression. Single-cell analysis revealed that DXM remodeled the immune microenvironment, enhancing NK cell cytotoxicity, and promoting M1-like macrophage polarization. These immunostimulatory effects were abrogated in STING-deficient models. Pharmacological inhibition of PP1 with salubrinal recapitulated DXM's effects, synergized with bortezomib to prolong survival in vivo, and enhanced daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC).

Conclusions: This study uncovers a glucocorticoid-sensitive inhibitory axis wherein GR-PPP1CB constitutively suppresses STING-TBK1-IRF3 signaling in MM. DXM relieves this suppression, reactivating innate anti-tumor immunity. PP1 inhibition represents a promising therapeutic strategy to enhance anti-myeloma immunity and overcome immune evasion.