Defining the tumor microenvironment of non-small cell lung cancer

Lung cancer is the most frequent cause of cancer-related mortality globally. In recent years, the treatment landscape for advanced-stage non-small-cell lung cancer (NSCLC) has been transformed by the advent of immunotherapy, which has yielded unprecedented and durable clinical responses for some patients. This shift has powered a significant expansion of novel immunotherapeutic strategies in oncology over the past few decades, heralding a new direction in the management of NSCLC. Despite these advances, only a fraction of patients acquire sustained benefit from immunotherapy, while the majority often develop resistance, resulting in disease progression leading to death. Several factors may contribute to this limited success, notably tumor heterogeneity and the intricate composition of the tumor microenvironment (TME). As a result, it is imperative to fully dissect the heterogeneity of the TME by identifying the principal drivers of cancer progression and immunotherapy resistance. This understanding is crucial for optimizing individualized treatment approaches. Here, we provide a summary of NSCLC, discuss the cardinal features of the TME and review advanced technologies such as spatial profiling of tissues, which are useful in dissecting the dynamicity of the tumor ecosystem. In addition, we highlight the recent developments and future perspectives of immunotherapy and other emerging therapeutics, as well as the role of predictive biomarker testing to ensure tailored therapy and tackle drug resistance, on the pathway to precision medicine.