{
  "abstract": "Background Acquired resistance to KRAS G12C inhibitor sotorasib remains a critical challenge in non-small cell lung cancer treatment. A deeper, rational understanding of resistance mechanisms can enable the development of therapeutic strategies to overcome resistance.Methods We established a syngeneic resistant model after prolonged AMG-510 treatment in C57BL/6 mice. In addition, the in vitro co-culture model and multiple methods including flow cytometry and western blot were used to assess the changes of immune microenvironment during resistance. Finally, a serial combinatorial therapy strategy was applied in the resistant mouse model to evaluate its ability to reverse resistance.Results Upregulation of PD-L1 in KRAS G12C tumors drives an immunosuppressive tumor microenvironment and promotes acquired resistance characterized by reduced infiltration of cytotoxic CD8+ T cells and a marked expansion of myeloid-derived suppressor cells through JAK2/STAT3/IL-6 Pathway. These mechanisms promote tumor immune evasion and protection from cell apoptosis, thereby establishing a microenvironment that sustains acquired resistance to sotorasib. Critically, sequential administration of a PD-L1 inhibitor (PD-L1i) effectively reprogrammed the immunosuppressive microenvironment, restoring antitumor immunity and re-sensitizing resistant tumors to sotorasib treatment.Conclusions These results identify the PD-L1-driven immunosuppressive microenvironment as a key mediator of sotorasib resistance and propose PD-L1i as a synergistic strategy to overcome resistance, which warrants clinical exploration of sequential or combinatorial regimens.",
  "authors": [
    {
      "affiliations": [
        "Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China",
        "Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, Liaoning, China"
      ],
      "name": "Shougeng Liu"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China",
        "Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, Liaoning, China"
      ],
      "name": "Yiting Jiang"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China",
        "Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, Liaoning, China"
      ],
      "name": "Yudong Fu"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China",
        "Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, Liaoning, China"
      ],
      "name": "Simeng Wang"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China",
        "Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, Liaoning, China"
      ],
      "name": "Rao Fu"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China",
        "Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, Liaoning, China"
      ],
      "name": "Minmin Gao"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China",
        "Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, Liaoning, China"
      ],
      "name": "Yingxi Zhao"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China",
        "Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, Liaoning, China"
      ],
      "name": "Sihong Chen"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China",
        "Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, Liaoning, China"
      ],
      "name": "Yuan Yang"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China",
        "Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, Liaoning, China"
      ],
      "name": "Weiming Yang"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China",
        "Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, Liaoning, China"
      ],
      "name": "Lina Jia"
    },
    {
      "affiliations": [
        "Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning, China"
      ],
      "name": "Mingze Qin"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China"
      ],
      "name": "Xiaohui Zhang"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China",
        "Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, Liaoning, China"
      ],
      "name": "Wei Cui"
    },
    {
      "affiliations": [
        "Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China",
        "Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, Liaoning, China"
      ],
      "name": "Lihui Wang"
    }
  ],
  "title": "Tumor immune microenvironment facilitates resistance to KRAS G12C inhibitor sotorasib by altered PD-L1 expression.",
  "uid": "790f2df0-9326-5e36-8915-67278c271233"
}