Synergistic Enhancement of Hydrophobic Tag with Low‐Temperature Photothermal Technique for Cancer Therapy

Abstract Hydrophobic tag (HyT) protein degraders hold significant promise for drug development; however, their limited degradative efficiency remains a major challenge. In this study, it is identified that heat‐induced upregulation of HSP70, particularly Hspa1a and Hspa1b, enhances protein degradation by HyT while simultaneously exacerbating heat‐induced cytotoxicity. A functionalized nanoplatform, JQ‐NP@PDA is presented, which integrates a photothermal agent polydopamine (PDA) with the protein degrader JQ‐HyT. This platform enables low‐temperature photothermal therapy (LTPTT) in conjunction with bromodomain‐containing protein 4 (BRD4) degradation for cancer treatment. JQ‐NP@PDA demonstrate synergistic therapeutic efficacy, exhibiting enhanced apoptotic effects induced by LTPTT alongside improved BRD4 degradation mediated by JQ‐HyT, compared to the individual administration of JQ‐HyT or LTPTT. Furthermore, increased infiltration of immune cells and the down‐regulation of programmed cell death ligand 1 contribute to the efficacy of tumor therapies. The elevated expression of heat shock protein 70 (HSP70) is found to promote BRD4 degradation, while the thermal damage repair function of HSP70 is effectively inhibited by JQ‐HyT. This dual mechanism significantly overcomes the therapeutic limitations associated with either approach when used in isolation. Overall, this approach not only advances the development of HyT‐based protein degraders but also enhances the efficacy of LTPTT. The combination therapy proposed in this study holds potential for broader applications in cancer treatment.