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Publications

Journal Article Ppublish

PubMed: 42170265 DOI: 10.21037/tlcr-2025-aw-1173

TLR7 induces autophagy in non-small cell lung cancer tumor cells and influences anti-tumors responses in patients.

Transl Lung Cancer Res 15(4):75

Authors: Lucas Leonardi, Solenne Marmier, Nathalie Josseaume, Sophie Sibéril, Mathilde Prieto, Karen Leroy, Audrey Mansuet-Lupo, Diane Damotte, Marco Alifano, Isabelle Cremer, Pierre-Emmanuel Joubert

Affiliations

  • Team Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cite, Paris, France.
  • Department of Thoracic Surgery, Hôpital Cochin, Assistance Publique Hôpitaux de Paris Centre, Université Paris Cité, Paris, France.
  • Department of Biochemistry, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris Centre, Université Paris Cité, Paris, France.
  • Team Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cite, Paris, France. Departments of Pathology and Thoracic Surgery, Hôpital Cochin, Assistance Publique Hôpitaux de Paris Centre, Université Paris Cité, Paris, France.

Abstract

BACKGROUND

Autophagy is a fundamental catabolic process with context-dependent roles in cancer. In non-small cell lung cancer (NSCLC), its clinical significance and therapeutic implications remain unclear. Toll-like receptor 7 (TLR7) has been implicated in the modulation of tumor-immune interactions, but its connection to autophagy and treatment response has not been defined. Here, we aimed to investigate whether TLR7 signaling regulates autophagy in NSCLC and to determine its impact on tumor progression and therapeutic responses.

METHODS

We combined transcriptomic analyses of multiple NSCLC patient cohorts with in vitro and ex vivo functional assays to investigate the relationship between TLR7 activation and autophagy. Gene expression profiling was used to assess the presence of TLR7 ligands and autophagy signatures in the tumor microenvironment (TME). Associations between tumor autophagy levels, clinical outcomes, and therapeutic responses were evaluated retrospectively in independent cohorts.

RESULTS

Our analyses revealed that endogenous TLR7 ligands are present in the NSCLC TME, where they activate autophagy in malignant cells. High tumor TLR7-dependent autophagy was associated with poor prognosis and reduced sensitivity to platinum-based chemotherapy. Conversely, elevated autophagy correlated with improved responses to nivolumab, an anti-programmed death-1 (PD-1) immunotherapy. Mechanistic studies demonstrated that TLR7-induced autophagy promotes resistance to cisplatin (Cis.) and oxaliplatin (Oxali.) while upregulating PD-L1 expression, establishing a direct link between autophagy and therapeutic outcomes.

CONCLUSIONS

These findings identify TLR7-driven autophagy as a novel pathogenic pathway in NSCLC and a clinically relevant determinant of treatment response. This mechanism provides new insight into how tumor-intrinsic innate signaling shapes sensitivity to chemotherapy and immunotherapy, offering potential targets for therapeutic modulation.

MeSH

Toll-Like Receptors, Cells, Lung, Autophagy, Neoplasms, Carcinoma, Non-Small-Cell Lung, Drug Therapy, Immunotherapy, Lung Neoplasms, Small Cell Lung Carcinoma, Therapeutics, Ligands, Chemotherapy