HSP90 inhibitors in cancer immunotherapy: Therapeutic opportunities and challenges

Abstract

Heat shock protein 90 (HSP90), a highly evolutionarily conserved molecular chaperone, plays critical roles in both physiological processes and disease pathogenesis, with particularly prominent involvement in cancer initiation and progression. Emerging evidence highlights the multifaceted functions of HSP90 within the tumor immune microenvironment, including mediation of immune evasion mechanisms, induction of tolerance/suppressive phenotypes, and facilitation of angiogenesis and metastatic dissemination. Notably, aberrant HSP90 accumulation (intracellularly and extracellularly) drives oncogenic signaling and promotes tumor survival and metastasis through immunomodulatory mechanisms. The pharmacological inhibition of HSP90 demonstrates dual therapeutic benefits: selective targeting of malignant cells and reprogramming of the immunosuppressive tumor niche, thereby exhibiting remarkable translational potential. In cancer immunotherapy, HSP90 inhibitors synergize with immune checkpoint blockade, chemotherapy, radiotherapy, and hyperthermia therapy by enhancing tumor immunogenicity and eliciting robust antitumor immune responses. Furthermore, the ongoing development of isoform-selective inhibitors and dual-targeting agents represents a paradigm shift toward precision therapies that maximize efficacy while minimizing off-target effects. This review systematically examines HSP90's structural biology, its multifaceted immunoregulatory roles in malignancies, and the clinical promise of HSP90-targeted combinatorial immunotherapies. We further discuss emerging research frontiers and translational challenges, providing a strategic framework for advancing next-generation cancer immunotherapies.