HSP47 inhibition-induced CD155 expression through TRAF2 deubiquitination promotes tumor immune evasion

Heat shock protein 47 (HSP47) is crucial for protein quality control and tumor progression. While its role in cancer biology is well established, its impact on cancer immunity remains poorly understood. In this study, we aim to elucidate how HSP47 inhibition modulates immune evasion, with a specific focus on the CD155/T-cell immunoreceptor with Ig and ITIM domains (TIGIT) axis in osteosarcoma (OS).

We used OS cell lines and mouse models to examine the effects of HSP47 inhibition on tumor growth and immune response. Expression levels of CD155, TIGIT, and other immune checkpoint molecules were analyzed throughflow cytometry, immunofluorescence, and western blotting. We also assessed the therapeutic effects of combining HSP47 inhibition with CD155 blockade or nuclear factor-kappa B (NF-κB) inhibitors in preclinical models.

Inhibition of HSP47 resulted in increased expression of the immune checkpoint molecule CD155, which impaired the antitumor activity of CD8⁺ T cells through the TIGIT receptor. Mechanistically, HSP47 inhibition reduced TRAF2 ubiquitination, leading to enhanced NF-κB signaling and upregulation of CD155 in OS cells. Combining HSP47 inhibition with anti-TIGIT antibodies or the NF-κB inhibitor bortezomib significantly suppressed OS progression and improved survival in mouse models.

HSP47 inhibition promotes immune evasion by upregulating CD155 via the TRAF2-NF-κB pathway, which impairs CD8⁺ T cell-mediated antitumor immunity. The combination of HSP47 inhibition with CD155/TIGIT blockade enhances therapeutic efficacy, suggesting a promising strategy for combination cancer therapies.