CD8+组织驻留记忆T细胞和肿瘤浸润淋巴细胞（TILs）会调控肿瘤免疫和免疫监视。对Trm细胞和TILs的表征有助于确定潜在的增强抗肿瘤免疫的策略。在这里，我们发现转录因子SCML4对Trm细胞的进程和多功能性起到必需的作用，并与癌症患者的良好预后相关。此外，SCML4还能维持TILs的多种功能。在小鼠CD8+细胞中增加SCML4的表达显着减少了多种类型的肿瘤的生长，而SCML4的缺失则减弱了抗肿瘤免疫并促进CD8+ T细胞的耗竭。机械地说，SCML4将HBO1-BRPF2-ING4复合物招募到T细胞特异性基因的表达重编程中，从而增强了Trm细胞和TILs的存活和效应功能。脂肪酸代谢通过mTOR-IRF4-PRDM1信号通路促进SCML4的表达，并诱导脂肪酸代谢引发Trm细胞和TILs中组织驻留和多功能基因表达的表观遗传修饰。SCML4通过提高TILs中效应分子的表达和抑制TILs的凋亡来增强抗PD-1治疗的治疗效果，通过添加H3K14乙酰去乙酰化抑制剂可以进一步增强该效应。这些结果提供了肿瘤定位的Trm细胞和TILs功能调控的机械性观点，并确定了肿瘤免疫治疗的一个重要激活靶点。

CD8+ tissue-resident memory T (Trm) cells and tumor-infiltrating lymphocytes (TILs) regulate tumor immunity and immune surveillance. Characterization of Trm cells and TILs could help identify potential strategies to boost antitumor immunity. Here, we found that the transcription factor SCML4 was required for the progression and polyfunctionality of Trm cells and was associated with a better prognosis in patients with cancer. Moreover, SCML4 maintained multiple functions of TILs. Increased expression of SCML4 in CD8+ cells significantly reduced the growth of multiple types of tumors in mice, while deletion of SCML4 reduced antitumor immunity and promotes CD8+ T-cell exhaustion. Mechanistically, SCML4 recruited the HBO1-BRPF2-ING4 complex to reprogram the expression of T-cell-specific genes, thereby enhancing the survival and effector functions of Trm cells and TILs. SCML4 expression was promoted by fatty acid metabolism through mTOR-IRF4-PRDM1 signaling, and fatty acid metabolism induced epigenetic modifications that promoted tissue-resident and multifunctional gene expression in Trm cells and TILs. SCML4 increased the therapeutic effect of anti-PD-1 treatment by elevating the expression of effector molecules in TILs and inhibiting the apoptosis of TILs, which could be further enhanced by adding an inhibitor of H3K14ac deacetylation. These results provide a mechanistic perspective of functional regulation of tumor-localized Trm cells and TILs and identify an important activation target for tumor immunotherapy.