Cellular plasticity and non-small cell lung cancer: role of T and NK cell immune evasion and acquisition of resistance to immunotherapies

• Published in: Cancer and metastasis reviews 2025-03, Vol.44 (1), p.27, Article 27
• Main Authors: Mestiri, Sarra, Sami, Ana, Sah, Naresh, El-Ella, Dina Moustafa Abo, Khatoon, Sabiha, Shafique, Khadija, Raza, Afsheen, Mathkor, Darin Mansor, Haque, Shafiul
• Format: Article
• Language: English
• Subjects: Adaptability; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - therapy; CD8 antigen; Cell Plasticity - immunology; Cytotoxicity; Drug Resistance, Neoplasm - immunology; Effector cells; Epigenetics; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunological memory; Immunoregulation; Immunotherapy; Immunotherapy - methods; Invasiveness; Killer Cells, Natural - immunology; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lung Neoplasms - therapy; Lymphocytes; Lymphocytes B; Lymphocytes T; Macrophages; Memory cells; Natural killer cells; Non-small cell lung carcinoma; Oncology; Plasticity; Review; Small cell lung carcinoma; Suppressor cells; T-Lymphocytes - immunology; Tumor Escape; Tumor microenvironment; Tumor Microenvironment - immunology; Tumors
• ISSN: 0167-7659; 1573-7233; 1573-7233
• DOI: 10.1007/s10555-025-10244-8

Lung cancer is a leading global cause of mortality, with non-small cell lung cancer (NSCLC) accounting for a significant portion of cases. Immune checkpoint inhibitors (ICIs) have transformed NSCLC treatment; however, many patients remain unresponsive. ICI resistance in NSCLC and its association with cellular plasticity, epithelial-mesenchymal transition (EMT), enhanced adaptability, invasiveness, and resistance is largely influenced by epigenetic changes, signaling pathways, tumor microenvironment, and associated immune cells, fibroblasts, and cytokines. Immunosuppressive cells, including M2 tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, contribute to resistance by suppressing the immune response. This cellular plasticity is influenced when B cells, natural killer cells, and T cells are exhausted or inhibited by components of the tumor microenvironment. Conversely, diverse T cell, NK cell, and B cell subsets hold potential as predictive response markers particularly cytotoxic CD8 + T cells, effector memory T cells, activated T cells, tumor infiltrated NK cells, tertiary lymphoid structures, etc. influence treatment response. Identifying specific gene expressions and immunophenotypes within T cells may offer insights into early clinical responses to immunotherapy. ICI resistance in NSCLC is a multifaceted process shaped by tumor plasticity, the complex tumor microenvironment, and dynamic immune cell changes. Comprehensive analysis of these factors may lead to the identification of novel biomarkers and combination therapies to enhance ICI efficacy in NSCLC treatment.