Targeting TBK1 potentiates oncolytic virotherapy via RIPK1-ICAM1 mediated NK killing in chemo-resistant colorectal cancer [scRNA-seq]

Acquired chemo-resistance poses a significant challenge in cancer therapy and is a leading cause of cancer mortality. To address this issue, we explored the therapeutic potential of using oncolytic viruses (OVs) to combat chemo-resistant colorectal cancer (CRC). However, the sensitivities to different OVs, including VSVΔ51 and HSV-1, were significantly reduced in chemo-resistant CRC. Our investigation revealed that elevated TANK-binding kinase 1 (TBK1) expression in chemo-resistant CRC mediated the activation of the type I interferon pathway, which impaired viral replication and oncolysis. Inhibition of TBK1 enhanced viral replication and the antitumor efficacy of VSVΔ51 by amplifying RIPK1-mediated necroptosis both in vitro and in vivo. Analysis of immune cell profiles demonstrated that the combination treatment reshaped the tumor microenvironment and increased the influx and functional activity of natural killer (NK) cells. Immune cell depletion studies indicated that NK cells were essential for the synergistic therapeutic activity of the combination treatment. Mechanistically, TBK1 inhibitors synergized with VSVΔ51 to increase ICAM1 expression in a RIPK1-dependent manner, promoting NK cell-mediated killing. This study presents a promising approach for treating chemo-resistant CRC by combining OVs and TBK1 inhibitors.