{
  "abstract": "Lack of sustained response to oncogenic Kras (Kras*) inhibition in preclinical models and patients with pancreatic ductal adenocarcinoma (PDAC) emphasizes the need to identify impactful synergistic combination therapies to achieve robust clinical benefit. Kras* targeting results in an influx of T cell infiltrates including Tregs, effector CD8 + T cells and exhausted CD8 + T cells expressing several immune checkpoint molecules in PDAC. Here, we probe whether the T cell influx induced by different Kras* inhibitors enable a therapeutic window to prime adaptive immune response in PDAC. Here we report a specific synergy between Kras G12D allele specific inhibitor, MRTX1133 or multi-selective pan-RAS inhibitor, RMC-6236 and anti-CTLA4 immune checkpoint blockade. In contrast, attempted therapeutic combination with multiple other immune checkpoint inhibitors, including anti-PD1, anti-Tim3, anti-Lag3, anti-Vista and anti-4-1BB agonist antibody failed due to compensatory mechanisms mediated by other checkpoints on exhausted CD8 + T cells. Specifically, anti-CTLA4 therapy in Kras* targeted PDAC transcriptionally reprograms effector T regs to a naïve phenotype, reverses CD8 + T cell exhaustion and is associated with recruitment of tertiary lymphoid structures (TLS) containing follicular B cells, interferon (IFN)- stimulated/ activated B cells, plasma cells and germinal center B cells to functionally enable efficacy of immunotherapy with long-term survival. In this regard, inhibition of the TLS with lymphotoxin-β inhibitor (LTBi) or direct B cell depletion reversed the survival benefit conferred by the combination therapy and highlights the function of TLS in generating productive anti-tumor immune responses. Further, single cell ATAC sequencing analysis revealed that transcriptional reprogramming of Tregs is epigenetically regulated by downregulation of AP-1 family of transcription factors including Fos, Fos-b, Jun-b, Jun-d in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with relevant clinical implications.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA",
    "Departments of Anatomical Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA",
    "Department of Investigative Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA",
    "Insititute for Applied Science and TRACTION platform, University of Texas MD Anderson Cancer Center, Houston, TX, USA",
    "Department of Bioengineering, Rice University, Houston, TX, USA. rkalluri@mdanderson.org",
    "Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. rkalluri@mdanderson.org",
    "Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. rkalluri@mdanderson.org",
    "Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA. rkalluri@mdanderson.org"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Krishnan K. Mahadevan",
      "orcid": "0000-0002-6503-6851"
    },
    {
      "affs": [
        0
      ],
      "name": "Ana S. Maldonado"
    },
    {
      "affs": [
        0
      ],
      "name": "Bingrui Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Aaron A. Bickert"
    },
    {
      "affs": [
        0
      ],
      "name": "Adrian Perdyan",
      "orcid": "0000-0002-5098-4357"
    },
    {
      "affs": [
        0
      ],
      "name": "Shreyasee V. Kumbhar"
    },
    {
      "affs": [
        1
      ],
      "name": "Sujan Piya",
      "orcid": "0000-0002-8976-540X"
    },
    {
      "affs": [
        0
      ],
      "name": "Amari M. Sockwell",
      "orcid": "0009-0008-1963-4181"
    },
    {
      "affs": [
        0
      ],
      "name": "Sami J. Morse",
      "orcid": "0009-0001-2796-2010"
    },
    {
      "affs": [
        0
      ],
      "name": "Kent A. Arian"
    },
    {
      "affs": [
        0
      ],
      "name": "Hikaru Sugimoto",
      "orcid": "0000-0003-0499-3962"
    },
    {
      "affs": [
        0
      ],
      "name": "Shabnam Shalapour",
      "orcid": "0000-0002-4743-3706"
    },
    {
      "affs": [
        2
      ],
      "name": "David S. Hong",
      "orcid": "0000-0001-8721-1609"
    },
    {
      "affs": [
        3
      ],
      "name": "Timothy Paul Heffernan",
      "orcid": "0000-0002-3166-8922"
    },
    {
      "affs": [
        1
      ],
      "name": "Anirban Maitra",
      "orcid": "0000-0001-7923-9978"
    },
    {
      "affs": [
        4,
        5,
        6,
        7
      ],
      "name": "Raghu Kalluri",
      "orcid": "0000-0002-2190-547X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/38kwat3cars5x.bib",
  "cited_by": 11,
  "doi": "10.1038/s41467-026-75960-3",
  "fulltext_url": null,
  "id": "38kwat3cars5x",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://doi.org/10.1038/s41467-026-75960-3",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7171360267",
  "pdf_url": null,
  "pmcid": "PMC11908235",
  "pmid": "40093186",
  "published": "2026-07-27",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/38kwat3cars5x.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T13:21:15Z",
      "native_id": "W7171360267",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41467-026-75960-3"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Cancer Immunotherapy and Biomarkers",
      "subfield": "oncology"
    }
  ],
  "title": "Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer",
  "title_text": "Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T13:21:16Z",
  "url": "https://research.draconitic.com/paper/38kwat3cars5x",
  "venue": "Nature Communications",
  "versions": []
}