Signal transducer and activator of transcription 3 (STAT3)/Cyclin‐dependent kinases are multifunctional proteins that play an important implicative role in cancer initiations, progression, drug resistance, and metastasis, and has been extensively explored in cancer therapy. However, the genetic alterations of STAT3/CDK2/4/6 and its role in predicting immune infiltration and immuno-therapeutic response are yet to be well exploited. In this study, we use in silico methods to analyze differential expression, prognostic value, genetic and epigenetic alterations, association with tumor-infiltrating immune cells, and cancer‐associated fibroblast (CAF) infiltrations of STAT3/CDK2/4/6 in multiple cancer types. Our results revealed that the expression of STAT3/CDK2/4/6 was altered in various cancers and is associated with poor overall and disease‐free survival of the cohorts. More-over, genetic alterations in STAT3/CDK2/4/6 co‐occurred with a number of other genetic alterations and are associated with poorer prognoses of the cohorts. The protein‐protein interaction (PPI) network analysis suggests CDK2/4/6/STAT3 may directly interact with factors that promote tumor-igenesis and immune response. We found that STAT3/CDK2/4/6 expressions were associated with infiltrations of CAF and the various immune cells in multiple cancers and it’s associated with poor response to immunotherapy. Collectively, our study suggested that STAT3/CDK2/4/6 are important onco‐immune signatures that play central roles in tumor immune invasion, poor prognoses and, immune therapy response. Findings from the present study may therefore be clinically useful in prognosis assessment and follow‐up management of immunotherapy.
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