Targeting proteasome composition reprograms tumor-intrinsic inflammation through selective degradation of STAT1

A covalent small molecule that binds a dynamic pocket in the non-catalytic proteasome regulator PSME4 reprograms tumor-intrinsic inflammation. Blocking or reducing PSME4 with the probe and orthogonal genetic perturbations stabilized STAT1, restored interferon-associated transcription, enhanced antigen presentation, and disrupted IL-6/STAT3 signaling, suppressing tumor growth in vivo. The work defines a PSME4-STAT1-STAT3 axis and a framework for drugging non-catalytic proteasome regulators to alter tumor immunity.