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CDK4\/6 inhibitor (CDK4\/6i) induces antitumor immune phenotypes by targeting both tumor and immune cells, enhancing immune checkpoint blockade (ICB), but optimal combination modalities and the corresponding cellular mechanisms remain unclear. Here, it is shown that activation of tumor cell\u2010intrinsic cyclin D1\u2010CDK4\/6 signaling is associated with low tumor\u2010infiltrating lymphocyte populations and immunotherapy resistance in head and neck squamous cell carcinoma (HNSCC). Comparison of sequential versus combinatorial regimens in subcutaneous or orthotopic HNSCC mice revealed that CDK4\/6i priming before anti\u2010PD\u20101 enhances response durability by promoting CD8\n                    <jats:sup>+<\/jats:sup>\n                    and CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell infiltration and decreasing overall neutrophil abundance. Mechanistically, IL15\u2010secreted Sell(hi) neutrophils induced Stat5a+ progenitor exhausted CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells contributed to the antitumor effect of CDK4\/6i priming modalities. Together with corroborating evidence from a clinically relevant patient\u2010derived\u2010organoid\u2010TIL (PDO\u2010TIL) co\u2010culture model, these findings support further clinical testing of brief CDK4\/6i dosing before anti\u2010PD\u20101 to improve ICB efficacy.\n                  <\/jats:p>","DOI":"10.1002\/advs.202510501","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T03:54:04Z","timestamp":1757649244000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["CDK4\/6 Inhibitor Priming Enhances PD\u20101 Blockade via Sell\n                    <sup>hi<\/sup>\n                    Neutrophil\u2010Induced Stat5a\n                    <sup>+<\/sup>\n                    Progenitor Exhausted CD8\n                    <sup>+<\/sup>\n                    T 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