Fig. 7

Schematic of proposed mechanism for CDK4/6 inhibitors’ effects on surface immune molecules in KSHV⁺ cells and EBV⁺ cells. In addition to direct inhibition of tumor cell proliferation, CDK4/6 inhibitors downregulate DNA methyltransferase 1, which activates both ERVs and certain KSHV/EBV genes. The DNA and RNA viral elements stimulate IFNs, which activate transcription factors including STAT1 and NLRC5. These genes in turn transactivate the expression of ISGs and immune surface molecules including MHC-I, ICAM-1, B7-2, and PD-L1. These surface molecules enable killing of the tumor by binding to receptors on T cells and potentially NK cells too. Because expression of PD-L1 is also enhanced, the results suggest that it may be worth testing CDK4/6 inhibitors with anti-PD1/L1 therapy