To confirm the crucial role of XBP1s in mediating resistance to CDK4/6 inhibitors and endocrine therapy, we assessed the responsiveness of HR+/HER2− breast cancer to the combined therapy of palbociclib and fulvestrant, with or without 4μ8C‐mediated blockade of XBP1 splicing, in PDO‐0912 and PDO‐3890 models. This evidence concerns the gene CDK4 and breast cancer.