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Hepatocellular carcinoma (HCC) poses a significant clinical challenge, necessitating the integration of immunotherapeutic approaches. Palbociclib, a selective CDK4/6 inhibitor, has demonstrated promising efficacy in preclinical HCC models and is being evaluated as a novel therapeutic option in clinical trials. Additionally, CDK4/6 inhibition induces cellular senescence, potentially influencing the tumor microenvironment and immunogenicity of cancer cells. In this study, we conducted comprehensive bioinformatic analyses using diverse HCC transcriptome datasets, including bulk and single-cell RNA-sequencing data from public databases. We also utilized human and mouse HCC cells to investigate functional aspects. Primary T cells isolated from mouse blood were employed to assess T cell immunity against HCC cells. Results revealed that CD8+ T-cell infiltration correlates with improved outcomes in HCC patients with suppressed CDK4/6 expression. Moreover, CDK4/6 expression was associated with alterations in the immune landscape and immune checkpoint expression within the liver tumor microenvironment. Furthermore, we found that treatment with Palbociclib and Doxorubicin induces cellular senescence and a senescence-associated secretory phenotype in HCC cells. Notably, pretreatment with Palbociclib augmented T cell-mediated cytotoxicity against HCC cells, despite upregulation of PD-L1, surpassing the effects of Doxorubicin pretreatment. In conclusion, our study elucidates a novel mechanism by which CDK4/6 inhibition enhances T-cell-associated cancer elimination and proposes a potential therapeutic strategy to enhance T-cell immunotherapy on HCC. [ABSTRACT FROM AUTHOR]