{
  "abstract": "Background Adoptive T-cell therapy has emerged as a promising therapeutic strategy for cancer treatment. However, clinical challenges persist, including the limited ability of CD8+T cells to infiltrate solid tumors and efficiently eliminate tumor cells. Given the critical role of epigenetic mechanisms in antitumor immunity, targeting epigenetic regulators represents a critical step toward optimizing adoptive T-cell therapies for solid tumors.Methods To investigate the role of KMT5A in CD8+T cell function, we employed CRISPR screening to identify KMT5A as a negative regulator. We then genetically deleted KMT5A in human CD8+T cells and systematically evaluated its impact on the antitumor efficacy of chimeric antigen receptor (CAR)-T cells using xenograft models. Furthermore, we used the small-molecule inhibitor UNC0379 to pharmacologically inhibit KMT5A, meticulously assessing the consequent effects on CAR-T cell activation, cytotoxicity, and antitumor activity.Results We report that lysine methyltransferase KMT5A acts as a negative regulator of CD8+T cell function, identified via CRISPR screening. KMT5A deletion in human CD8+T cells significantly enhances the antitumor efficacy of CAR CD8+T cells in xenograft models. In vitro immunophenotyping reveals that KMT5A deletion improves effector functions, cytokine secretion, and early activation of CD8+T cells. Mechanistically, KMT5A depletion increases the expression and chromatin accessibility of multiple effector-related genes in CD8+T cells. KMT5A-mediated histone H4 modifications and chromatin remodeling suppress CD8+T cell effector functions, partially via inhibition of the transcription factor SP1. Notably, pharmacological inhibition of KMT5A using the small-molecule inhibitor UNC0379 enhanced activation, cytotoxicity, and antitumor activity in human CD8+T cells—a novel finding in this study.Conclusions Our findings establish KMT5A as an epigenetic regulator that impairs CD8+T cell function. These findings demonstrate that genetic or pharmacological (eg, UNC0379) targeting of KMT5A in CD8+T cells represents a viable therapeutic strategy to augment effector functions and improve adoptive T-cell therapies, particularly CAR-T cells, for solid tumors.",
  "authors": [
    {
      "affiliations": [
        "East China Normal University, Shanghai, China"
      ],
      "name": "Xiaoling Tian"
    },
    {
      "affiliations": [
        "East China Normal University, Shanghai, China"
      ],
      "name": "Guolong Liu"
    },
    {
      "affiliations": [
        "East China Normal University, Shanghai, China"
      ],
      "name": "Qiudao Wang"
    },
    {
      "affiliations": [
        "BRL Medicine, Inc, Shanghai, China"
      ],
      "name": "Na Zhang"
    },
    {
      "affiliations": [
        "East China Normal University, Shanghai, China"
      ],
      "name": "Yanting Shen"
    },
    {
      "affiliations": [
        "East China Normal University, Shanghai, China"
      ],
      "name": "Bing Du"
    },
    {
      "affiliations": [
        "East China Normal University, Shanghai, China",
        "YolTech Therapeutics, Shanghai, China"
      ],
      "name": "Yuxuan Wu"
    }
  ],
  "title": "Genome editing or small molecule inhibition of KMT5A in CAR-T cells enhances antitumor immunity",
  "uid": "0c32e379-efb9-5937-876b-1be9c8237e75"
}