Heat Shock Proteins in Cancer: Mechanisms and Therapeutic Targeting.

Authors

Sheng Ma, Chen-Qian Liu, Si-Yang Ma, Shao-Gang Wang, Qi-Dong Xia, Meng-Yao Xu

Published in

MedComm. Volume 7. Issue 9. Pages e70966. Epub Sep 11, 2026.

Abstract

Heat shock proteins (HSPs) are molecular chaperones that couple proteostasis to cancer metabolic reprogramming under oncogenic and microenvironmental stress. This Review integrates structural, biochemical, preclinical, and clinical evidence on HSP90, HSP70, HSP60, HSP40, HSP110, and small HSPs. We explain how ATPase cycles, chaperonin cages, co-chaperone networks, and organelle-specific localization stabilize metabolic enzymes, glucose transporters, hypoxia-responsive factors, and electron-transport-chain components, thereby coordinating glycolysis, mitochondrial bioenergetics, redox homeostasis, lipid metabolism, and metabolic plasticity. These mechanisms enable tumor survival and therapy resistance but also create context-dependent vulnerabilities. We critically evaluate pan-HSP and isoform-selective inhibitors, disruption of chaperone-client or co-chaperone interfaces, HSP-directed immunotherapies, and biomarker-guided combinations with metabolic or immune therapies. Clinical translation remains limited by systemic toxicity, compensatory heat-shock responses, tumor-type heterogeneity, and the absence of validated predictive biomarkers. We also assess circulating HSPs, cryo-EM analysis of chaperone complexes, and AI-assisted ligand design as routes for biomarker development and selective drug discovery. By linking chaperone architecture and client specificity to metabolic outputs and cancer phenotypes, this Review establishes a framework for differentiating actionable HSP dependencies from observational associations. It further defines priorities for patient stratification and precision oncology, supporting the development of selective and tractable strategies that target proteostasis-metabolism coupling.

PMID:
42732222
Bibliographic data and abstract were imported from PubMed on 13 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.