Bridging BET bromodomain and immune checkpoint inhibitors through generative bioorganic frameworks for next-generation cancer immunotherapy.

Abstract

Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that couple chromatin acetylation to oncogenic and immune-regulatory gene transcription, making them attractive targets for combination with immune checkpoint inhibitors (ICIs) in precision oncology. This review synthesizes current mechanistic, medicinal-chemistry, and translational evidence on BET-ICI combination strategies. We describe how BET blockade reshapes tumor chromatin architecture, suppresses PD-L1 expression, and enhances antigen presentation, thereby increasing tumor susceptibility to immune-mediated attack. We further summarize preclinical efficacy data for BET-ICI combinations, including systems-biology and agent-based computational models that predict substantially greater tumor-volume reduction with combination regimens relative to monotherapy in selected preclinical settings; however, early-phase clinical experience with these combinations remains limited and has not yet reproduced this magnitude of benefit. Beyond the mechanism, we review the medicinal chemistry underlying BET inhibitor design and the emerging landscape of BET-ICI hybrid and conjugate therapeutics, distinguishing combinations with direct experimental support from conceptual pairings that remain hypothesis-generating. Finally, we discuss how systems biology and generative, AI-guided molecular design may inform resistance-mechanism prediction, toxicity mitigation, and biomarker-guided, patient-specific compound selection. Collectively, this review outlines a framework for how the convergence of epigenetic reprogramming, immune modulation, and generative bioorganic chemistry could inform the rational design of next-generation BET-ICI combination therapeutics.