CD73 targeted combination therapy reverses PD-1 inhibitor resistance in CD73-high PD-L1-negative NSCLC: Evidence from pleural effusion organoids.
4 affiliations
- 1Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
- 2Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
- 3School of Medicine, South China University of Technology, Guangzhou, China.
- 4Shantou University Medical College, Shantou, Guangdong, China.
Abstract
Objectives
Patients with PD-L1-negative non-small cell lung cancer (NSCLC) often exhibit inherent PD-1 inhibitor resistance, leading to poor monotherapy efficacy and unfavorable clinical outcomes. Notably, no effective stratification biomarkers are currently available to overcome this resistance. Thus, this study aimed to reverse PD-1 inhibitor resistance in PD-L1-negative NSCLC by identifying novel predictive biomarkers and developing effective targeted immunotherapeutic regimens.Methods
Pleural effusion-derived organoids (PEOs) were established and validated from driver gene wild-type, PD-L1-negative NSCLC patients. Four treatment groups were set: control, anti-PD-1 monotherapy (Toripalimab), anti-CD73 monotherapy (Uliledlimab), and anti-PD-1 + anti-CD73 combination (Toripalimab + Uliledlimab). ATP assay was used to detect tumor cell viability. Spearman's rank correlation analysis was applied to evaluate the association between CD73 expression and tumor inhibition rates. Flow cytometry was employed to measure T cell activation markers. Enzyme-linked Immunospot assay was used to detect IFN-γ and TNF-α secretion.Results
PEO models recapitulated the biological features of primary pleural effusion. Toripalimab monotherapy showed no antitumor efficacy in PD-L1-negative subgroup regardless of CD73 expression levels, whereas Toripalimab + Uliledlimab combination significantly reversed PD-1 inhibitor resistance in CD73-high PD-L1-negative NSCLC patients. Furthermore, a significant positive correlation was observed between CD73 expression levels and tumor inhibition rates.Conclusion
This study validates CD73 as a potential predictive biomarker for stratifying PD-L1-negative NSCLC patients and establishes anti-PD-1+ anti-CD73 combination regimen that effectively reverses PD-1 inhibitor resistance in CD73-high PD-L1-negative NSCLC patients.
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BibTeX
@article{ren2026cd73,
title = {{CD73 targeted combination therapy reverses PD-1 inhibitor resistance in CD73-high PD-L1-negative NSCLC: Evidence from pleural effusion organoids.}},
author = {Zi-Rui Ren and Lv Wu and Qian-Lin Huang and Dong-Xuan Cai and Ying-Long Peng and Li-Bo Tang and Jia-Ting Li and Hong-Yi Zhu and Chong-Rui Xu and Chang Lu and Zhi-Hong Chen and Yu Deng and Yu-Jie Lin and Qing Zhou},
journal = {Global medical genetics},
year = {2026},
month = oct,
doi = {10.1016/j.gmg.2026.100142},
url = {https://europepmc.org/article/MED/42927277},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - CD73 targeted combination therapy reverses PD-1 inhibitor resistance in CD73-high PD-L1-negative NSCLC: Evidence from pleural effusion organoids.
AU - Zi-Rui Ren
AU - Lv Wu
AU - Qian-Lin Huang
AU - Dong-Xuan Cai
AU - Ying-Long Peng
AU - Li-Bo Tang
AU - Jia-Ting Li
AU - Hong-Yi Zhu
AU - Chong-Rui Xu
AU - Chang Lu
AU - Zhi-Hong Chen
AU - Yu Deng
AU - Yu-Jie Lin
AU - Qing Zhou
PY - 2026
DA - 2026/10/12
JO - Global medical genetics
DO - 10.1016/j.gmg.2026.100142
UR - https://europepmc.org/article/MED/42927277
AB - Objectives Patients with PD-L1-negative non-small cell lung cancer (NSCLC) often exhibit inherent PD-1 inhibitor resistance, leading to poor monotherapy efficacy and unfavorable clinical outcomes. Notably, no effective stratification biomarkers are currently available to overcome this resistance. Thus, this study aimed to reverse PD-1 inhibitor resistance in PD-L1-negative NSCLC by identifying novel predictive biomarkers and developing effective targeted immunotherapeutic regimens.Methods Pleural effusion-derived organoids (PEOs) were established and validated from driver gene wild-type, PD-L1-negative NSCLC patients. Four treatment groups were set: control, anti-PD-1 monotherapy (Toripalimab), anti-CD73 monotherapy (Uliledlimab), and anti-PD-1 + anti-CD73 combination (Toripalimab + Uliledlimab). ATP assay was used to detect tumor cell viability. Spearman's rank correlation analysis was applied to evaluate the association between CD73 expression and tumor inhibition rates. Flow cytometry was employed to measure T cell activation markers. Enzyme-linked Immunospot assay was used to detect IFN-γ and TNF-α secretion.Results PEO models recapitulated the biological features of primary pleural effusion. Toripalimab monotherapy showed no antitumor efficacy in PD-L1-negative subgroup regardless of CD73 expression levels, whereas Toripalimab + Uliledlimab combination significantly reversed PD-1 inhibitor resistance in CD73-high PD-L1-negative NSCLC patients. Furthermore, a significant positive correlation was observed between CD73 expression levels and tumor inhibition rates.Conclusion This study validates CD73 as a potential predictive biomarker for stratifying PD-L1-negative NSCLC patients and establishes anti-PD-1+ anti-CD73 combination regimen that effectively reverses PD-1 inhibitor resistance in CD73-high PD-L1-negative NSCLC patients.
SN - 2699-9404
ER -