show Abstracthide AbstractTargeting chromatin binding proteins and modifying enzymes can concomitantly affect tumor cell proliferation and survival, as well as enhance anti-tumor immunity and augment cancer immunotherapies. By screening a small molecule library of epigenetics-based therapeutics, BET bromodomain inhibitors (BETi) were identified as agents that sensitize tumor cells to the anti-tumor activity of CD8+ T-cells. BETi modulated tumor cells to be sensitized to the cytotoxic effects of the pro-inflammatory cytokine TNF. By preventing the recruitment of BRD4 to p65-bound cis-regulatory elements, BETi suppressed the induction of inflammatory gene expression, including the key NF-?B target genes BIRC2 (cIAP1) and BIRC3 (cIAP2). Disruption of pro-survival NF-?B signaling by BETi led to unrestrained TNF-mediated activation of the extrinsic apoptotic cascade and tumor cell death. Administration of BETi in combination with T-cell bispecific (TCB) antibodies increased bystander killing of tumor cells and enhanced tumor growth inhibition in vivo in a TNF-dependent manner. This novel epigenetic mechanism of immunomodulation may guide future use of BETi as adjuvants for immune oncology agents. Overall design: RNA-sequencing of E0771 and MC38 cells treated with TNF alone or in combination with clinical BET Bromodomain inhibitor RG6146.