Tissue-resident memory T cells (Trm) represent a diverse cell type with tissue-specific gene signatures that can operate as both effector and memory T cells. Trm cells play a crucial role in immune defense against infections and cancer. Recently, Trm cells have become appreciated as a critical responder to checkpoint immunotherapy and as a biomarker of favorable outcomes in cancer. Hence, it is of great clinical and therapeutic importance to investigate how Trm cells can be manipulated transcriptionally, epigenetically, or metabolically to improve their longevity and function. In this issue of Cancer Research, Feng and colleagues demonstrate that the transcription factor SCML4 is essential for the development and polyfunctionality of Trm cells. Fatty acids mediated the upregulation of SCML4 via the mTOR–IRF4–PRDM1 signaling pathway, which significantly enhanced tumor control in multiple aggressive murine tumor models and was associated with a favorable prognosis for patients with cancer. The findings also suggest that SCML4-mediated engagement of the HBO1–BRPF2–ING4 complex epigenetically reprogramed Trm cells by increasing the expression of several survival- and effector-associated molecules while blocking the expression of checkpoint inhibitors. Overall, Feng and colleagues highlight a critical activation target for tumor immunotherapy and provide a molecular perspective on recruiting antitumor Trm cells to the tumor niche by regulating fatty acids.