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Cancer-Associated-Fibroblast-Derived Small Extracellular Vesicles (sEVs) in Lung Cancer Immunotherapy Resistance:
Shuangrui Chen1,2, Jin Yan3, Xiaochun Peng1,2
1Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434020, China.
Abstract:
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.
Insights
Cancer-associated fibroblast-derived small extracellular vesicles (CAF-sEVs) promote lung cancer immunotherapy resistance by suppressing T-cell activity. Targeting CAF-sEVs offers a potential strategy to enhance treatment efficacy.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Immunotherapy is a key lung cancer treatment, but resistance limits its effectiveness.
- Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) mediate this resistance, partly via secreted small extracellular vesicles (sEVs).
- CAF-derived sEVs (CAF-sEVs) are implicated in immunotherapy resistance, with elevated levels correlating to poor patient response.
Purpose of the Study:
- To review the biophysical properties and molecular mechanisms of CAF-sEVs in lung cancer immunotherapy resistance.
- To critically evaluate the causal evidence linking CAF-sEVs to resistance and assess their limitations.
- To explore the translational potential of CAF-sEVs as biomarkers and therapeutic targets.
Main Methods:
- Comprehensive literature review synthesizing existing research on CAF-sEVs.
- Analysis of molecular pathways and functional effects of CAF-sEVs on the TME.
- Evaluation of preclinical data and clinical correlations.
Main Results:
- CAF-sEVs possess specific biophysical properties that facilitate their immunomodulatory functions.
- CAF-sEVs directly suppress T-cell activity and promote pro-resistance phenotypes through defined molecular mechanisms.
- Pharmacological inhibition of sEV secretion shows promise in preclinical models for overcoming resistance.
Conclusions:
- CAF-sEVs play a significant role in mediating lung cancer immunotherapy resistance.
- Further in vivo studies are needed to confirm the independent effects of CAF-sEVs.
- CAF-sEVs represent promising diagnostic biomarkers and therapeutic targets for improving lung cancer immunotherapy outcomes.
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