Harnessing an immunocompetent model of HR+ mammary carcinogenesis that recapitulates key immunobiological features of its human counterpart,6 as well as clinical samples from no less than 6 distinct cohorts of patients with HR+HER2− breast cancer, we have recently identified a novel immunological mechanism of adaptive resistance to CDK4/6 inhibitors that involves interleukin 17 (IL17)-secreting γδ T cells and C-X3-C motif chemokine receptor 1 (CX3CR1)-expressing tumor-associated macrophages (TAMs).7 The gene discussed is CDK4; the disease is breast cancer.