BET inhibition synergizes with RLR signaling to enhance tumor immunogenicity and T cell recognition.

Intratumoral signaling via the cytosolic double-stranded RNA (dsRNA) receptors RIG-I and MDA-5 enhance antitumor immunity and can overcome resistance to cancer immunotherapy. Although BET proteins are established epigenetic drivers of immune escape mechanisms, their role in regulating RIG-I-like receptor (RLR) signaling remains undefined. Therefore, we investigated the role of BET proteins in modulating innate antiviral responses to cytosolic dsRNA in tumor cells and how BET inhibition combined with dsRNA stimulation influences tumor immunogenicity and recognition by T cells. To address this, human tumor cell lines were treated with the BET inhibitor JQ1 and transfected with the synthetic viral dsRNA analog poly(I:C) to stimulate innate antiviral signaling. We found that BET inhibition synergistically amplifies dsRNA-induced immunogenicity, as indicated by enhanced cytokine and chemokine production, JAK-STAT signaling, antigen presentation, and immunogenic cell death. Combined treatment of melanoma cells with JQ1 and poly(I:C) resulted in a marked, synergistic enhancement of recognition by autologous tumor-specific CD8+ TIL, immunogenic cell death and maturation of dendritic cells. Furthermore, an antiviral gene signature induced by poly(I:C) and enhanced by JQ1 correlated with immune infiltration and improved survival in larger patient cohorts across different types of cancer. Overall, our findings demonstrate that targeting BET proteins in tumor cells strongly potentiates dsRNA-induced antiviral responses and suggests that combining BET inhibitors with RLR agonists offers a pharmacological strategy to enhance antitumor T cells responses and improve the clinical efficacy of cancer immunotherapies.