Cancer-Associated-Fibroblast-Derived Small Extracellular Vesicles (sEVs) in Lung Cancer Immunotherapy Resistance: Mechanistic Insights, Clinical Translations, and Current Challenges

Immunotherapy has emerged as an established clinical approach for lung cancer; however, both intrinsic and adaptive resistance mechanisms substantially constrain its therapeutic efficacy. Within the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) serve as pivotal stromal mediators of this resistance. These fibroblasts manifest their immunomodulatory effects, in part, through the secretion of small extracellular vesicles (sEVs). While multiple lines of evidence strongly implicate CAF-sEVs in immunotherapy resistance, establishing a direct causal link remains an active area of investigation. Clinically, elevated levels of specific CAF-sEV cargoes correlate with poor response in lung cancer patients. Functionally, CAF-sEVs can directly suppress T-cell activity and drive pro-resistance phenotypes via defined molecular pathways, and pharmacological inhibition of sEV secretion has been shown to attenuate resistance in preclinical models. However, the extent to which these effects are independent of other CAF-derived factors remains to be fully elucidated in vivo. This review comprehensively synthesizes the biophysical properties of CAF-derived sEVs, delineates the molecular mechanisms underpinning their role in immunotherapy resistance, critically evaluates the existing causal evidence and its limitations, and assesses their translational potential as diagnostic biomarkers and therapeutic targets—ultimately providing a conceptual framework to overcome resistance barriers in lung cancer immunotherapy.