Targeting HSP90 in cancer: advances in the development of inhibitors, mechanisms of action, and therapeutic applications.

Heat shock protein 90 (HSP90) serves as a central orchestrator of oncogenic protein homeostasis, empowering tumor progression, metastasis, and therapy resistance. However, the clinical translation of HSP90 inhibition has been hampered by challenges such as intrinsic and acquired resistance, a lack of reliable biomarkers, and the toxicity associated with pan-inhibitors. This review comprehensively dissects these challenges and presents the evolving landscape of strategies to overcome them. We systematically catalog the development of over 20 representative HSP90 inhibitors, from classical N-terminal ATP-competitive agents to novel C-terminal and middle-domain binders, highlighting their distinct mechanisms and the rise of subtype-selective compounds designed to enhance therapeutic windows. Beyond monotherapy, we emphasize the paradigm shift towards combination regimens, detailing synergistic effects with chemotherapy, targeted agents, and immunotherapies that resensitize tumors to treatment. Critically, we explore the diagnostic frontier, reviewing how radiolabeled HSP90 inhibitors (e.g., [¹²⁴I]PU-H71 and [¹⁸F]San A derivatives) enable non-invasive tumor detection and patient stratification through positron emission tomography (PET). Finally, we chart the future course of the field, underscoring how precision medicine approaches—guided by biomarker identification and liquid biopsy—coupled with nanotechnology-driven delivery systems, are poised to unlock the full potential of HSP90-targeted cancer theranostics. This synthesis provides not only a mechanistic overview but also a strategic roadmap for the next generation of HSP90-directed oncology research.