Lung tumour secretome and extracellular vesicles: mechanisms, biomarkers, and therapeutic opportunities

Abstract

Lung cancer progression is governed not only by tumour-intrinsic genetic alterations but also by dynamic communication between tumour cells and the surrounding microenvironment. An important component of this communication is the tumour secretome, comprising soluble factors and extracellular vesicles (EVs), which contribute to the regulation of tumour growth, invasion, immune evasion, and therapeutic resistance. Through these mechanisms, secretome components and EVs promote phenotypic plasticity, microenvironmental remodelling, and adaptive responses to hypoxia, immune surveillance, and therapeutic stress. Importantly, secretome-derived factors and EVs are released into accessible biofluids, including blood, bronchoalveolar lavage fluid, and pleural effusions, highlighting their potential as minimally invasive biomarkers. In this review, we examine the lung tumour secretome, including both soluble secreted factors and EVs, with an emphasis on their contributions to tumour progression, metastasis, immune modulation, and resistance to targeted therapies, immunotherapy, and radiation. We discuss methodological advances and persistent technical challenges in EV isolation, characterisation, and molecular profiling that influence reproducibility and interpretation. We further evaluate emerging clinical applications, including liquid biopsy, treatment monitoring, and therapeutic targeting, and consider their integration within precision oncology frameworks. Finally, we highlight key barriers to clinical translation and outline priorities for future research, including methodological standardisation, prospective clinical validation, and the development of strategies to target tumour-derived secretory signalling selectively.