Exogenous Heat Shock Proteins in Oncology: Biological Roles and Clinical Implications

Heat shock proteins (HSPs), particularly HSP70 and HSP90, are highly conserved molecular chaperones that protect cells from a wide range of stressors and maintain proteome homeostasis. In cancer, tumor cells frequently overexpress and actively release HSPs into the extracellular space and circulation in response to metabolic alterations, hypoxia, oxidative stress, and therapeutic interventions. Consequently, circulating HSP levels are often elevated in patients with malignancies compared with healthy individuals. This review summarizes current evidence on the diagnostic, prognostic, and predictive value of circulating HSPs in both solid and hematological cancers. Clinical studies indicate that circulating HSP concentrations are associated with tumor type, disease stage, lymph node involvement, metastatic burden, treatment response, and risk of recurrence. Importantly, membrane-associated and extracellular vesicle-associated forms of HSP70 appear to exhibit greater tumor specificity than freely circulating proteins, highlighting the importance of selecting appropriate analytical approaches for biomarker assessment. Beyond their utility as biomarkers, extracellular HSPs actively participate in tumor biology and anti-tumor immunity. Depending on the cellular and immunological context, they can either support tumor progression or stimulate immune responses through activation of natural killer cells, antigen-presenting cells, and cross-presentation of tumor-derived antigens. These immunomodulatory properties have provided the foundation for the development of HSP-based vaccines and adoptive immunotherapeutic strategies, several of which have demonstrated encouraging results in clinical trials. We further discuss the relationship between extracellular chaperone biology and responses to major anticancer treatments, including radiotherapy, chemotherapy, HSP90-targeted therapies, and immune checkpoint blockade. In conclusion, the available evidence supports circulating extracellular HSPs as promising non-invasive biomarkers and potential pharmacodynamic indicators that may improve patient stratification, treatment monitoring, and prediction of therapeutic efficacy in clinical oncology.