Reversing Tumor Therapy Resistance—Mechanistic Insights from Heat Shock Protein 90 and Frontiers in Drug Development

Tumor therapy resistance has emerged as a major challenge in clinical oncology, and is closely associated with approximately 90% of cancer-related deaths. Heat shock protein 90 (HSP90), a central component of the molecular chaperone system, serves as a key mediator in drug resistance through diverse mechanisms. These include stabilizing oncogenic client proteins, activating compensatory signaling pathways, promoting DNA repair, modulating tumor immunity, and facilitating metabolic reprogramming. This article systematically reviews the involvement of HSP90 in tumor therapy resistance and explores recent advances in HSP90-targeted drug development strategies. These encompass traditional N-terminal ATP-competitive inhibitors, C-terminal inhibitors, isoform-selective inhibitors, dual-target inhibitors, as well as emerging approaches such as targeting HSP90-co-chaperone interactions, chaperone-retention effect drug conjugates (CREDC), and chaperone-mediated protein degraders. Together, these strategies aim to provide new theoretical foundations and strategic directions for overcoming tumor therapy resistance.