The study investigates the anti-tumor immune effects of CDK4/6 inhibitors, which are known to induce cell cycle arrest in tumor cells. Using murine models of breast carcinoma and other solid tumors, the researchers found that these inhibitors not only arrest tumor cell cycles but also enhance anti-tumor immunity. This effect is attributed to two main mechanisms: first, CDK4/6 inhibitors activate the expression of endogenous retroviral elements, leading to increased production of type III interferons and enhanced tumor antigen presentation. Second, they suppress the proliferation of regulatory T cells (Tregs), which are immunosuppressive. Mechanistically, these effects are associated with reduced activity of the E2F target, DNA methyltransferase 1 (DNMT1). The findings suggest that CDK4/6 inhibitors can increase tumor immunogenicity and could be combined with immunotherapies to improve cancer treatment outcomes. The study also includes transcriptomic analysis from a clinical trial of CDK4/6 inhibitor treatment for breast cancer, supporting the clinical relevance of these findings.The study investigates the anti-tumor immune effects of CDK4/6 inhibitors, which are known to induce cell cycle arrest in tumor cells. Using murine models of breast carcinoma and other solid tumors, the researchers found that these inhibitors not only arrest tumor cell cycles but also enhance anti-tumor immunity. This effect is attributed to two main mechanisms: first, CDK4/6 inhibitors activate the expression of endogenous retroviral elements, leading to increased production of type III interferons and enhanced tumor antigen presentation. Second, they suppress the proliferation of regulatory T cells (Tregs), which are immunosuppressive. Mechanistically, these effects are associated with reduced activity of the E2F target, DNA methyltransferase 1 (DNMT1). The findings suggest that CDK4/6 inhibitors can increase tumor immunogenicity and could be combined with immunotherapies to improve cancer treatment outcomes. The study also includes transcriptomic analysis from a clinical trial of CDK4/6 inhibitor treatment for breast cancer, supporting the clinical relevance of these findings.