The tumor microenvironment (TME) is crucial for the onset, development, and resistance to treatment of lung cancer. The tumor microenvironment consisting of a complex array of immune cells, fibroblasts, endothelial cells, extracellular matrix elements, and signaling molecules, facilitates tumor growth and spread while inhibiting the body’s antitumor immune response. In lung cancer, tumor-associated macrophages, cancer-associated fibroblasts, mast cells, and dendritic cells interact through cytokines, chemokines, growth factors, and matrix metalloproteinases to create an immunosuppressive and proangiogenic milieu. Hypoxic conditions within the TME further enhance cancer cell adaptability through hypoxia-inducible factors (HIFs), promoting epithelial–mesenchymal transition, immune evasion, and metastasis. Moreover, miRNAs have emerged as key regulators of gene expression within the TME, offering novel insights into tumor behavior and potential therapeutic targets. Targeting dynamic interactions within the TME, particularly through the modulation of immune responses, angiogenesis, and stromal remodeling, offers promising avenues for precision pharmacological approaches. This review covers the current understanding of the lung TME, highlighting its impact on cancer pathophysiology and treatment strategies. Understanding and therapeutically reprogramming the TME may pave the way for personalized and more effective interventions for lung cancer treatment.

The tumor microenvironment (TME) plays a pivotal role in the initiation, progression, and therapeutic resistance of lung cancer. Comprising a complex network of immune cells, fibroblasts, endothelial cells, extracellular matrix components, and signaling molecules, the TME supports tumor survival and metastasis while suppressing anti-tumor immunity. In lung cancer, tumor-associated macrophages, cancer-associated fibroblasts, mast cells, and dendritic cells interact through cytokines, chemokines, growth factors, and matrix metalloproteinases to shape an immunosuppressive and pro-angiogenic milieu. Hypoxic conditions within the TME further enhance cancer cell adaptability through hypoxia-inducible factors (HIFs), promoting epithelial-mesenchymal transition, immune evasion, and metastatic potential. Moreover, microRNAs have emerged as key regulators of gene expression within the TME, offering novel insights into tumor behavior and potential targets for therapy. Targeting the dynamic interactions within the TME—especially through modulation of immune responses, angiogenesis, and stromal remodeling—offers promising avenues for precision pharmacology. This review summarizes current knowledge of the lung TME, highlighting its impact on cancer patho-physiology and treatment strategies. Understanding and therapeutically reprogramming the TME may pave the way for personalized and more effective interventions in lung cancer management.