{
  "abstract": "Background Although immunotherapy has revolutionized cancer treatment, its efficacy in castration-resistant prostate cancer (CRPC) remains limited, largely due to an immunologically “cold” tumor microenvironment with scarce T-cell infiltration. Unraveling the molecular mechanisms underlying immune evasion and developing novel strategies to activate innate antitumor immunity are therefore critical to overcoming immunotherapy resistance in CRPC.Methods Using bioinformatic approaches, we analyzed the protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) expression and its correlation with immune cell infiltration and response to immune checkpoint blockade (ICB) in public databases. PKMYT1 protein expression was further evaluated via immunohistochemistry in a clinical cohort of prostate cancer (PCa) specimens. Mechanistic investigations were conducted in PCa cell lines and mouse models. The immunological impact of PKMYT1 inhibition was delineated using single-cell RNA sequencing, and the therapeutic efficacy of RP-6306, either as monotherapy or in combination with programmed death-ligand 1 (PD-L1) blockade, was evaluated in syngeneic mouse models.Results PKMYT1 expression was significantly overexpressed in CRPC compared with primary PCa. High PKMYT1 expression correlated with a suppressed antitumor immunity and poor clinical response to ICB. Mechanistically, PKMYT1 inhibition activated the cyclic guanosine monophosphate-adenosine monophosphate adenosine synthase (cGAS)-stimulator of interferon genes (STING) pathway, potentiated both type I and II interferon signaling, and upregulated chemokines, including CCL5 and CXCL10. The selective PKMYT1 inhibitor, RP-6306, enhanced the efficacy of ICB in the presence of CD8 + T cells. Treatment with a PKMYT1 inhibitor alone or in combination with PD-L1 blockade significantly increased the infiltration of activated CD8+ T cells and induced significant tumor suppression in vivo.Conclusion PKMYT1 is a pivotal dual regulator of tumor progression and immune evasion in CRPC. Our findings provide a compelling preclinical rationale for targeting PKMYT1 as a novel strategy to reprogram the tumor immune microenvironment and overcome resistance to immunotherapy.",
  "authors": [
    {
      "affiliations": [
        "Department of Pathology & Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China",
        "School of Life Sciences and Health, University of Health and Rehabilitation Sciences, Qingdao, Shandong, China"
      ],
      "name": "Lin Gao"
    },
    {
      "affiliations": [
        "Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China"
      ],
      "name": "Baozhen Wang"
    },
    {
      "affiliations": [
        "Department of Pathology, Qilu Hospital of Shandong University, Jinan, Shandong, China"
      ],
      "name": "Hui Liu"
    },
    {
      "affiliations": [
        "Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China"
      ],
      "name": "Ping Liu"
    },
    {
      "affiliations": [
        "Department of Pathology, Qilu Hospital of Shandong University, Jinan, Shandong, China"
      ],
      "name": "Long Liu"
    },
    {
      "affiliations": [
        "Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China"
      ],
      "name": "Jingying Han"
    },
    {
      "affiliations": [
        "Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China"
      ],
      "name": "Xin Wang"
    },
    {
      "affiliations": [
        "Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China"
      ],
      "name": "Baokai Dou"
    },
    {
      "affiliations": [
        "Department of Pathology, Peking University People’s Hospital, Beijing, China"
      ],
      "name": "Feifei Sun"
    },
    {
      "affiliations": [
        "Department of Pathology, Qilu Hospital of Shandong University, Jinan, Shandong, China"
      ],
      "name": "Wenyao Liu"
    },
    {
      "affiliations": [
        "Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China"
      ],
      "name": "Xinpei Wang"
    },
    {
      "affiliations": [
        "Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University, Jinan, Shandong, China"
      ],
      "name": "Tingting Feng"
    },
    {
      "affiliations": [
        "Department of Pathology, Qilu Hospital of Shandong University, Jinan, Shandong, China"
      ],
      "name": "Ru Zhao"
    },
    {
      "affiliations": [
        "Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong, China"
      ],
      "name": "Xiaorong Yang"
    },
    {
      "affiliations": [
        "Department of Pathology & Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China"
      ],
      "name": "Weiwen Chen"
    },
    {
      "affiliations": [
        "Department of Pathology, Qilu Hospital of Shandong University, Jinan, Shandong, China"
      ],
      "name": "Jing Hu"
    },
    {
      "affiliations": [
        "Department of Pathology, Peking University People’s Hospital, Beijing, China"
      ],
      "name": "Bo Han"
    }
  ],
  "title": "Targeting PKMYT1 enhances antitumor immune responses to PD-L1 blockade in castration-resistant prostate cancer",
  "uid": "e99cc34d-e340-551f-b8e8-d48e31e56b33"
}