Heat shock protein 70 (Hsp70) as a target for advancing immunotherapy in solid tumors.

Abstract

Heat shock protein 70 (Hsp70) is a highly conserved molecular chaperone that maintains protein homeostasis (proteostasis) under stress conditions. In cancer, Hsp70 is frequently overexpressed, where it contributes to hallmark features of malignancy by stabilizing oncogenic proteins, suppressing apoptosis, and promoting invasion and immune evasion. Beyond its intracellular functions, Hsp70 is aberrantly presented on the plasma membrane of a broad range of solid tumor cells and actively released into the extracellular space, either in soluble form or encapsulated within extracellular lipid microvesicles with biophysical characteristics of exosomes, supporting tumor microenvironment remodeling and immune modulation. The selective surface expression of Hsp70 on tumor cells, but not healthy tissues, defines it as a tumor-associated antigen (TAA) and an accessible target for immunotherapy. Leveraging this unique feature, several therapeutic approaches have been developed addressing membrane Hsp70 on tumor cells, including small molecule inhibitors, peptide-mediated activation of natural killer (NK) cells, monoclonal antibodies, fusion vaccines, and chimeric antigen receptor (CAR)-engineered immune cells. In parallel, extracellular Hsp70 in the blood is emerging as a promising liquid biomarker for patient stratification and treatment monitoring in cancer patients. This review outlines the context-dependent roles of Hsp70 in cancer and critically evaluates its translational potential as both a therapeutic target and diagnostic marker in solid tumors. We also discuss advances in detection technologies, findings from early-phase clinical trials, and persistent challenges such as off-target effects, tumor heterogeneity, and achieving effective and selective targeting.