Cancer cell-intrinsic features (e.g., genetic aberrations and dysregulation of signaling pathways) play pivotal roles in orchestrating the composition and functional state of the immune landscape, which in turn impact tumor progression and response to immunotherapy. 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). SMYD3 cooperates with Sp1 to transcriptionally promote sterol regulatory element-binding protein 1 (SREBP1) expression by modifying H3-K4 di-/trimethylation and consequently activating the transcription of CD47. CD47, a bridge between innate and adaptive immunity, acts as the downstream effector molecule of the SMYD3 signal to promote the infiltration of T helper 2 (Th2) cells, protecting renal cancer cells from immune attack. In summary, the critical role of the cancer cell-intrinsic SMYD3-SREBP1-CD47 axis is elucidated in regulating the immune microenvironment in ccRCC and provides a potential therapeutic strategy to manipulate the tumor immune milieu in favor of antitumor immunity.© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.