2. Academic Validation
  3. Tumor immune microenvironment facilitates resistance to KRAS G12C inhibitor sotorasib by altered PD-L1 expression

Tumor immune microenvironment facilitates resistance to KRAS G12C inhibitor sotorasib by altered PD-L1 expression

  • J Immunother Cancer. 2026 Feb 4;14(2):e012886. doi: 10.1136/jitc-2025-012886.
Shougeng Liu # 1 2,  Yiting Jiang # 1 2,  Yudong Fu 1 2,  Simeng Wang 1 2,  Rao Fu 1 2,  Minmin Gao 1 2,  Yingxi Zhao 1 2,  Sihong Chen 1 2,  Yuan Yang 1 2,  Weiming Yang 1 2,  Lina Jia 1 2,  Mingze Qin 3,  Xiaohui Zhang 4,  Wei Cui 5 2,  Lihui Wang 5 2
Affiliations

Affiliations

  • 1 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
  • 2 Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
  • 3 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
  • 4 Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China [email protected] [email protected] [email protected].
  • 5 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China [email protected] [email protected] [email protected].
  • # Contributed equally.
PMID: 41638869 DOI: 10.1136/jitc-2025-012886
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.

Keywords

Immune Checkpoint Inhibitor; Lung Cancer; T-Lymphocytes; Tolerance; Tumor microenvironment - TME.

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