Shikonin enhances the efficacy of PD-1 blockade in colorectal cancer by inducing immunogenic cell death

Abstract Background : PD-1 blockade has shown impressive clinical outcomes in colorectal cancers patients with high microsatellite instability (MSI-H). However, the majority of patients with colorectal cancer who present low microsatellite instability (MSI-L) or stable microsatellites (MSS) show little response to PD-1 blockade therapy. Here, we have demonstrated that Shikonin (SK) could induce cell death of CT26 cells via classically programmed and immunogenic pathways. Methods and Results : SK promoted the membrane exposure of calreticulin and upregulated the expression of heat shock protein 70 (Hsp70). The upregulation of Hsp70 was dependent on ROS induced by SK and silencing of PKM2 in CT26 cells reverts ROS upregulation. Besides, SK synergizes with PD-1 blockade in CT26 xenograft mice model, with the increase of intramural DC cells and CD8 + T cells. The expression of Hsp70 in tumor tissue was also increased in combinational SK plus αPD-1 therapy group. Conclusions : Our study elucidated the potential role of ‘Shikonin-PKM2-ROS-Hsp70-ICD’ axis in the promotion of efficacy of PD-1 blockade in CRC treatments, providing a potential strategy and targets for improving the efficacy of PD-1 blockade in colorectal cancer.