2. Academic Validation
  3. CRTC1 enhances PD-L1-mediated tumor immunosuppression in non-small cell lung cancer via the Notch1/Akt signaling pathway

CRTC1 enhances PD-L1-mediated tumor immunosuppression in non-small cell lung cancer via the Notch1/Akt signaling pathway

  • Front Immunol. 2025 Sep 5:16:1658679. doi: 10.3389/fimmu.2025.1658679.
Xujun Feng 1 2 3,  Yuan Shi 3,  Fang Yuan 4,  Yanxia Hu 4,  Xiangdong Tang 3,  Wei Zhang 1 5,  Jiadi Gan 6,  Longhua Sun 1,  Lingling Cao 2
Affiliations

Affiliations

  • 1 The Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
  • 2 Jiujiang City Key Laboratory of Cell Therapy, The First Hospital of Jiujiang City, Jiujiang, Jiangxi, China.
  • 3 Sleep Medicine Center, Department of Respiratory and Critical Care Medicine, Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 4 Department of Respiratory, The First Hospital of Jiujiang City, Jiujiang, Jiangxi, China.
  • 5 Jiangxi Provincial Key Laboratory of Respiratory Diseases, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.
  • 6 Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China.
PMID: 40977688 DOI: 10.3389/fimmu.2025.1658679
Abstract

Background: While programmed death-ligand 1 (PD-L1)-targeted immunotherapy represents an advancement in non-small cell lung Cancer (NSCLC), patient outcomes remain suboptimal. Aberrant activation of the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB)-regulated transcription coactivator (CRTC) is linked to malignant proliferation and functionality in lung Cancer cells. This study investigates the involvement of CRTC1 in tumor immunity.

Methods: CRTC1 and Notch1 expression were regulated in A549 and NCI-H1299 NSCLC lines through plasmid-mediated overexpression/silencing to assess their effects on cell viability, Apoptosis, migration, and invasion. CRTC1/Notch1-dysregulated Lewis lung carcinoma (LLC) cells were co-cultured with T cells to evaluate T cell activation and function. The efficacy of combined CRTC1 knockdown/overexpression and atezolizumab (anti-PD-L1) was tested in an LLC xenograft mouse model.

Results: CRTC1 promoted cell viability, migration, and invasion while suppressing Apoptosis across NSCLC models. In LLC cells, CRTC1 upregulated tumor cell PD-L1 expression, suppressed T cell-derived IFN-γ and IL-2 production, diminished endogenous CXCL10/11 secretion, and impaired T Cell Proliferation and Cytotoxicity. Mechanistically, CRTC1 interacted with Notch1 to activate the Notch1/Akt pathway, stimulating PD-L1 upregulation, thereby facilitating tumor immunosuppression and growth. Notably, CRTC1 overexpression reversed the protective effects of atezolizumab on tumor growth. Combining CRTC1 knockdown with atezolizumab synergistically enhanced anti-tumor T cell immunity, achieving the most significant tumor regression in xenografts.

Conclusion: These findings indicate that CRTC1 in tumor cells suppresses PD-L1-mediated anti-tumor immunity and promotes tumorigenesis via the Notch1/Akt signaling axis. Dual targeting of CRTC1 and PD-L1 demonstrates therapeutic synergy, suggesting CRTC1 pathway inhibition could optimize immunotherapy outcomes in NSCLC patients.

Keywords

CRTC; Notch/Akt signaling; immunosuppression; immunotherapy; non-small cell lung cancer.

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