Immunomodulatory role of oncogenic alterations in non-small cell lung cancer: a review of implications for immunotherapy

• Published in: Cancer and metastasis reviews 2025-03, Vol.44 (1), p.30, Article 30
• Main Authors: Ramos-Ramírez, Maritza, Caballe-Pérez, Enrique, Lucio-Lozada, José, Romero-Nuñez, Eunice, Castillo-Ruiz, Cesar, Dorantes-Sánchez, Lorena, Flores-Estrada, Diana, Recondo, Gonzalo, Barrios-Bernal, Pedro, Cabrera-Miranda, Luis, Bravo-Dominguez, Heyman, Hernández-Pedro, Norma, Arrieta, Oscar
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - therapy; Fibroblast growth factor receptor 1; Fibroblast growth factor receptor 4; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - therapeutic use; Immunomodulation; Immunomodulation - genetics; Immunotherapy; Immunotherapy - methods; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lung Neoplasms - therapy; Lymphocytes T; MAP kinase; Metastases; Mutation; Non-small cell lung carcinoma; Oncology; Patients; Phenotypes; Review; Small cell lung carcinoma
• ISSN: 0167-7659; 1573-7233; 1573-7233
• DOI: 10.1007/s10555-025-10245-7

Immune checkpoint inhibitors (ICIs) have improved clinical outcomes in patients with non-small cell lung cancer (NSCLC) lacking targetable oncogenic alterations. However, their efficacy in individuals with such genomic alterations remains heterogeneous and poorly understood. In detail, certain oncogenic alterations in TP53 , EGFR (uncommon mutations), KRAS (G12C), BRAF (non-V600E), MET (amplifications), FGFR1 and FGFR4 , actively modify MAPK, PI3K, and STING signaling, thus remodeling tumoral immune phenotype and are associated with high TMB counts, enriched T lymphocyte tumor infiltration, and high expression of antigen-presenting molecules, supporting their consideration as part of the eligibility criteria for ICIs treatment. Nonetheless, other oncogenic alterations are associated with an immunosuppressive TME, low TMB counts, and downregulation of targetable immune checkpoints, in which novel therapeutic approaches are currently being tested to overcome their intrinsic resistance. In this context, this review discusses the fundamental mechanisms by which frequent driver alterations affect ICIs efficacy in patients with NSCLC, and outlines their prognostic relevance in the era of immunotherapy.