A Ruthenium(II) Complex Inhibits BRD4 for Synergistic Seno‐ and Chemo‐Immunotherapy in Cisplatin‐Resistant Tumor Cells

Abstract Drug resistance is a significant challenge for tumor therapy. Activating immunity is an effective method to combat drug‐resistant tumors. Utilizing metallic chemotherapeutic agents to induce nonapoptotic programmed cell death is a practical approach to stimulate immunity. Besides, triggering tumor cell senescence, named senotherapy, is also an effective but often ignored method to induce immune responses. Despite some progress, reports on metallic immunotherapeutic stimuli are sparse and mainly delve into the level of organelle targeting, with vague drug–target mechanisms. Here, we report a Ru(II) complex ( Ru2c ) inhibits BRD4 with high affinity at a nanomolar constant. After encapsulation into biotin‐DNA cage, Ru2c@biotin‐DNA cage was demonstrated to kill drug‐resistant cancer cells through a synergistic apoptosis‐ferroptosis‐senescence pathway, exhibiting 51‐fold anticancer activity compared to the commercial inhibitor JQ‐1. Ru2c effectively erased drug‐resistant tumors and activated innate and acquired immunity in vivo. To the best of our knowledge, Ru2c is the first metal‐based BRD4 inhibitor to achieve synergistic seno‐immunotherapy and chemo‐immunotherapy.