Targeting HSP70 protein-protein interactions for cancer precision Therapy: Mechanisms, structures, and inhibitor strategies.

Dysregulated protein homeostasis and aberrant signaling pathways are established hallmarks of cancer. Among key molecular players, heat shock protein 70 (HSP70) exerts critical oncogenic functions by forming stable protein-protein interactions (PPIs) with co-chaperones and client proteins, thereby sustaining malignant signaling, suppressing apoptosis, and promoting drug resistance. However, conventional ATPase inhibitors targeting HSP70 face clinical limitations, including target conservation, systemic toxicity, and induction of the heat shock response. Inhibitors targeting HSP70 PPIs demonstrate superior selectivity, reduced toxicity, and enhanced resistance. This review systematically examines the mechanisms through which major HSP70-mediated PPIs drive tumor progression and treatment resistance. Furthermore, we provide structural insights into druggable PPI interfaces localized to the HSP70 nucleotide-binding domain (NBD) and C-terminal TPR-recognition motif, critically evaluating recent advances in the development of small-molecule and peptide-based PPI inhibitors. Together, these analyses offer new perspectives for advancing precision cancer therapeutics.