CD73 targeted combination therapy reverses PD-1 inhibitor resistance in CD73-high PD-L1-negative NSCLC: Evidence from pleural effusion organoids.

Authors

Zi-Rui Ren, Lv Wu, Qian-Lin Huang, Dong-Xuan Cai, Ying-Long Peng, Li-Bo Tang, Jia-Ting Li, Hong-Yi Zhu, Chong-Rui Xu, Chang Lu, Zhi-Hong Chen, Yu Deng, Yu-Jie Lin, Qing Zhou

Published in

Global medical genetics. Volume 13. Issue 4. Pages 100142. Epub Oct 12, 2026.

Abstract

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.
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.
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.
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.

PMID:
42927277
Bibliographic data and abstract were imported from PubMed on 25 Oct 2026.

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