In this context and consistent with recent evidence showing that the tumour microenvironment may limit the efficacy of a wide variety of breast cancer therapeutic approaches, including CDK/46 inhibitors [22–27], we also discuss evidence regarding the capacity of CDK4/6 inhibitors to induce the release of protumourigenic senescence-associated molecules as well as to exert context-dependent stimulatory effects on important TME components, namely, cancer-associated fibroblasts (CAFs). Here, CDK4 is linked to neoplasm.