HSP90 as an emerging barrier to immune checkpoint blockade therapy

Immunotherapy, especially the use of immune checkpoint inhibitors, has improved overall survival in cancer patients. However, a large proportion of patients initially do not respond to treatment or relapse after a period of response. Heat shock protein 90 (HSP90) is a conserved molecular chaperone that promotes the maturation and folding of substrate proteins involved in many different cellular pathways. Our recent drug screen and functional assay identified HSP90 as a universal control of the protein stability of nuclear transcription factor STAT1 in a variety of different cancer cells, thereby promoting subsequent gene expression of immune checkpoint molecules (IDO1 and PD-L1). In vivo, we used different mouse models of pancreatic cancer and demonstrated that targeting HSP90 enhanced the efficacy of PD-1 blockade therapy. These findings establish HSP90 as a targetable vulnerability in immune therapy.