Mestiri Sarra, Sami Ana, Sah Naresh, El-Ella Dina Moustafa Abo, Khatoon Sabiha, Shafique Khadija, Raza Afsheen, Mathkor Darin Mansor, Haque Shafiul
Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar.
Queen Mary University of London, London, UK.
Cancer Metastasis Rev. 2025 Jan 25;44(1):27. 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.
肺癌是全球主要的死亡原因，其中非小细胞肺癌（NSCLC）占很大比例。免疫检查点抑制剂（ICI）改变了NSCLC的治疗方式；然而，许多患者仍然没有反应。NSCLC中的ICI耐药性及其与细胞可塑性、上皮-间质转化（EMT）、增强的适应性、侵袭性和耐药性的关联在很大程度上受表观遗传变化、信号通路、肿瘤微环境以及相关免疫细胞、成纤维细胞和细胞因子的影响。免疫抑制细胞，包括M2肿瘤相关巨噬细胞、骨髓来源的抑制细胞和调节性T细胞，通过抑制免疫反应导致耐药。当B细胞、自然杀伤细胞和T细胞被肿瘤微环境成分耗竭或抑制时，这种细胞可塑性会受到影响。相反，多种T细胞、NK细胞和B细胞亚群具有作为预测反应标志物的潜力，特别是细胞毒性CD8 T细胞、效应记忆T细胞、活化T细胞、肿瘤浸润NK细胞、三级淋巴结构等会影响治疗反应。识别T细胞内的特定基因表达和免疫表型可能有助于深入了解免疫治疗的早期临床反应。NSCLC中的ICI耐药是一个由肿瘤可塑性、复杂的肿瘤微环境和动态免疫细胞变化所塑造的多方面过程。对这些因素进行综合分析可能会发现新的生物标志物和联合疗法，以提高ICI在NSCLC治疗中的疗效。
