Hsp90 pan and Isoform-Selective Inhibitors as Sensitizers for Cancer Immunotherapy

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Heat shock protein 90 (Hsp90) is crucial for cancer hallmark regulation.
• Pan-Hsp90 inhibitors face challenges due to toxicity and compensatory responses.
• Isoform-selective Hsp90 inhibitors are being developed to mitigate these issues.

Purpose of the Study:

• To review Hsp90 function, inhibition, and advances in isoform-selective targeting.
• To highlight the potential of Hsp90 inhibition in sensitizing tumors to cancer immunotherapy.
• To focus on Hsp90β-selective inhibitors for immune modulation without adverse effects.

Main Methods:

• Review of molecular mechanisms of Hsp90 function and inhibition.
• Analysis of recent advancements in isoform-selective Hsp90 inhibitors.
• Examination of preclinical and clinical data on Hsp90 inhibitors combined with immunotherapy.

Main Results:

• Hsp90 inhibition enhances tumor antigen presentation and immune activation.
• Isoform-selective inhibitors, particularly Hsp90β-selective ones, modulate immune pathways effectively.
• Combination therapy with Hsp90 inhibitors and immunotherapy shows potential against resistant and cold tumors.

Conclusions:

• Isoform-selective Hsp90 inhibitors offer a safer therapeutic strategy than pan-Hsp90 inhibitors.
• Targeting Hsp90 can potentiate cancer immunotherapy by overcoming resistance mechanisms.
• Further development of these inhibitors is a promising approach to improve cancer treatment efficacy.