Molecular Chaperone Targeting in Cancer Therapy

Molecular chaperones are essential regulators of cellular proteostasis, guiding the folding, maturation and degradation of nascent and stress-damaged proteins. Among these, heat shock proteins such as HSP90 and HSP70 oversee a vast repertoire of oncogenic clients including kinases, transcription factors and hormone receptors. Cancer cells exploit chaperone networks to sustain aberrant signalling, resist apoptosis and adapt to hostile microenvironments. Targeting these nodes can destabilise multiple pro-tumour pathways simultaneously and overcome resistance to conventional therapies. Strategies encompass ATP-competitive inhibitors, allosteric modulators, epichaperome chemical probes that bind pathological scaffolding assemblies, and nanotechnology-based delivery systems. Recent advances combine chaperone inhibition with immunotherapy to potentiate antitumour immunity and employ precision design to minimise systemic toxicity and avoid induction of heat shock responses. Collectively, the field is shifting from broad-spectrum blockade towards context-specific approaches that normalise protein-protein interaction networks, trigger immunogenic cell death and synergise with established treatments, offering promising avenues for clinical translation.

Research from Nature Portfolio

Recent studies have leveraged chemical binders of epichaperomes to perform proteome-wide mapping of protein-protein interaction dysfunctions in unmodified cancer cells. These analyses revealed context-dependent vulnerabilities in mitotic networks and provided mechanistic insight into tumour cell fitness, establishing a foundation for therapeutics aimed at restoring normal interactomes. In addition, inhibition of a principal chaperone was shown to upregulate interferon response genes, thereby enhancing T-cell-mediated killing of tumour cells and potentiating checkpoint-blockade efficacy. Together, these works illustrate how precise chaperone modulation can exert dual impacts on intrinsic tumour biology and the immune microenvironment, underscoring a move towards integrated treatment regimens.

Molecular Chaperone Targeting in Cancer Therapy publication trend

The graph below shows the total number of articles in molecular chaperone targeting in cancer therapy across all publications each year (not limited to Nature Index journals).

Technical terms

Molecular chaperone: A protein that assists the folding, unfolding and assembly of other proteins without being part of the final structure.

HSP90: Heat shock protein 90, an ATP-dependent chaperone that stabilises and activates numerous client oncoproteins.

Epichaperome: Pathological assemblies of chaperones and co-chaperones that rewire protein-protein interaction networks in disease contexts.

Nanoinhibitor: A nano-scale construct designed to deliver or enhance inhibitory action against specific molecular targets such as chaperones.

Pyroptosis: Pro-inflammatory programmed cell death characterised by gasdermin-mediated membrane pore formation and cytokine release.

Interferon response genes: Genes induced by interferon signalling that enhance antigen presentation and immune-mediated tumour eradication.

References

1. Systems-level analyses of protein-protein interaction network dysfunctions via epichaperomics identify cancer-specific mechanisms of stress adaptation. Nature Communications (2023).
2. HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes. Nature Communications (2017).
3. Metal-enriched HSP90 nanoinhibitor overcomes heat resistance in hyperthermic intraperitoneal chemotherapy used for peritoneal metastases. Molecular Cancer (2023).
4. The HSP90 inhibitor HVH-2930 exhibits potent efficacy against trastuzumab-resistant HER2-positive breast cancer. Theranostics (2024).