Here, it is discovered that dysregulation of cancer cell‐intrinsic SET and MYND domain‐containing protein 3 (SMYD3) leads to the orchestration of an immunosuppressive microenvironment and the impairment of responses to PD‐1 blockade by reprogramming the infiltration of immune cells in the tumor microenvironment of clear cell renal cell carcinoma (ccRCC). Here, SMYD3 is linked to neoplasm.