CDK4/6 Inhibitor Priming Enhances PD‐1 Blockade via Sell hi Neutrophil‐Induced Stat5a + Progenitor Exhausted CD8 + T Cell

Abstract Cell cycle pathway, especially via cyclin D1‐CDK4/6 signaling, is enriched in immunotherapy‐resistant and immune‐excluded tumors. 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‐intrinsic cyclin D1‐CDK4/6 signaling is associated with low tumor‐infiltrating 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‐PD‐1 enhances response durability by promoting CD8 + and CD4 + T cell infiltration and decreasing overall neutrophil abundance. Mechanistically, IL15‐secreted Sell(hi) neutrophils induced Stat5a+ progenitor exhausted CD8 + T cells contributed to the antitumor effect of CDK4/6i priming modalities. Together with corroborating evidence from a clinically relevant patient‐derived‐organoid‐TIL (PDO‐TIL) co‐culture model, these findings support further clinical testing of brief CDK4/6i dosing before anti‐PD‐1 to improve ICB efficacy.