T cells are central to all currently effective cancer immunotherapies, but the characteristics defining therapeutically effective anti-tumor T cells have not been comprehensively elucidated. Here, we delineate four phenotypic qualities of effective anti-tumor T cells: cell expansion, differentiation, oxidative stress, and genomic stress. Using a CRISPR-Cas9-based genetic screen of primary T cells we measured the multi-phenotypic impact of disrupting 25 T cell receptor-driven kinases. We identified p38 kinase as a central regulator of all four phenotypes and uncovered transcriptional and antioxidant pathways regulated by p38 in T cells. Pharmacological inhibition of p38 improved the efficacy of mouse anti-tumor T cells and enhanced the functionalities of human tumor-reactive and gene-engineered T cells, paving the way for clinically relevant interventions.

T 细胞是目前所有有效的癌症免疫疗法的核心，但定义治疗有效的抗肿瘤 T 细胞的特征尚未得到全面阐明。在这里，我们描述了有效抗肿瘤 T 细胞的四种表型品质：细胞扩增、分化、氧化应激和基因组应激。使用基于 CRISPR-Cas9 的原代 T 细胞遗传筛选，我们测量了破坏 25 个 T 细胞受体驱动激酶的多表型影响。我们确定 p38 激酶是所有四种表型的中心调节因子，并发现了 T 细胞中 p38 调节的转录和抗氧化途径。p38 的药理学抑制提高了小鼠抗肿瘤 T 细胞的功效，并增强了人类肿瘤反应性和基因工程 T 细胞的功能，