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.

Extracellular vesicles (EVs) are emerging as versatile mediators of intercellular communication and promising tools for drug discovery and targeted therapies. These lipid bilayer-bound nanovesicles facilitate the transfer of functional proteins, RNAs, lipids, and other biomolecules between cells, thereby influencing various physiological and pathological processes. This review outlines the molecular mechanisms governing EV biogenesis and cargo sorting, emphasizing the role of regulators, such as ubiquitin-like 3 (UBL3), in modulating protein packaging. We explored the critical involvement of EVs in various disease microenvironments, including cancer progression, neurodegeneration, and immune modulation. Their ability to cross biological barriers and deliver bio-active cargo renders them highly attractive for precise drug delivery systems, especially in neurological and oncological disorders. Moreover, this review highlights advances in engineering EVs for delivering RNA therapeutics, CRISPR-Cas systems, and targeted small molecules. The utility of EVs as diagnostic tools in liquid biopsies and their integration into personalized medicine and companion diagnostics were also discussed. Patient-derived EVs offer dynamic insights into disease state and enable real-time treatment stratification. Despite their potential, challenges such as scalable isolation, cargo heterogeneity, and regulatory ambiguity remain significant hurdles. We also reported novel pharmacological approaches targeting EV biogenesis, secretion, and uptake pathways, and considered UBL3 as a promising drug target for EV cargo modulation. Future directions include the standardization of EV analytics, scalable biomanufacturing, and classification of EV-based therapeutics under evolving regulatory frameworks. This review emphasizes the multifaceted roles of EVs and their transformative potential as therapeutic platforms and biomarker reservoirs in next-generation precision medicine.