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Immune checkpoint blockade therapies are still ineffective for most patients with colorectal cancer (CRC). Immunogenic cell death (ICD) enables the release of key immunostimulatory signals to drive efficient anti-tumor immunity, which could be used to potentiate the effects of immune checkpoint inhibitors. Here, we showed that inhibition of valosin-containing protein (VCP) elicits ICD in CRC. Meanwhile, VCP inhibitor upregulates PD-L1 expression and compromises anti-tumor immunity in vivo. Mechanistically, VCP transcriptionally regulates PD-L1 expression in a JAK1-dependent manner. Combining VCP inhibitor with anti-PD1 remodels tumor immune microenvironment and reduces tumor growth in mouse models of CRC. Addition of oncolytic virus further augments the therapeutic activity of the combination regimen. Our study shows the molecular mechanism for regulating PD-L1 expression by VCP and suggests that inhibition of VCP has the potential to increase the efficacy of immunotherapy in CRC. [Display omitted] • VCP inhibitor elicits ICD but induces immune escape through the upregulation of PD-L1 • VCP regulates PD-L1 expression via JAK1/STAT3 pathway • Combining VCP inhibitor and anti-PD1 provides therapeutic benefit • A triple combination of VCPI, anti-PD1, and VSVΔ51 further improves tumor response Wang et al. show that VCP inhibitor induces ICD but upregulates PD-L1 expression, impeding anti-tumor immune response. VCP regulates PD-L1 expression in a JAK1-dependent manner. Combining VCP inhibitor with anti-PD1 effectively reduces tumor growth in vivo. Addition of oncolytic virus further improves the therapeutic responses of the combination regimen. [ABSTRACT FROM AUTHOR]