COPD reshapes the tumor microenvironment of NSCLC and enhances anti-PD-1 therapy response.
Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in non-small cell lung cancer (NSCLC) and has been clinically associated with improved responses to programmed cell death protein-1 (PD-1) blockade. Whether this enhancement is directly attributable to COPD and the mechanisms driving it remains unclear.
We conducted an integrated translational study combining three clinical cohorts with multi-omics profiling, including single-cell RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence. Fresh surgical tumor specimens were subsequently used to perform in vitro functional assays to validate epithelial-immune interactions identified through multi-omics analyses.
COPD induces epithelial remodeling that expands a distinct basal-like tumor cell population with progenitor-like features in NSCLC. These cells activate a dominant CXCL14-CXCR4 signaling axis to preferentially recruit macrophages producing CXCL9, thereby establishing a localized microenvironment that is more permissive for cytotoxic T cell infiltration. This spatially restricted tumor-macrophage recruitment circuit was functionally validated and found to be enriched in patients with NSCLC who achieved a major pathological response following neoadjuvant anti-PD-1 therapy.
Our findings define a mechanistic link between COPD comorbidity and enhanced PD-1 blockade efficacy. The presence of this tumor-macrophage axis in patients with NSCLC with favorable immunotherapy outcomes highlights its translational potential as both a predictive biomarker and a therapeutic target to improve checkpoint blockade responsiveness.
This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0529403) and the National Natural Science Foundation of China (82370028, 82422001, 32330061, and 82303972).
We conducted an integrated translational study combining three clinical cohorts with multi-omics profiling, including single-cell RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence. Fresh surgical tumor specimens were subsequently used to perform in vitro functional assays to validate epithelial-immune interactions identified through multi-omics analyses.
COPD induces epithelial remodeling that expands a distinct basal-like tumor cell population with progenitor-like features in NSCLC. These cells activate a dominant CXCL14-CXCR4 signaling axis to preferentially recruit macrophages producing CXCL9, thereby establishing a localized microenvironment that is more permissive for cytotoxic T cell infiltration. This spatially restricted tumor-macrophage recruitment circuit was functionally validated and found to be enriched in patients with NSCLC who achieved a major pathological response following neoadjuvant anti-PD-1 therapy.
Our findings define a mechanistic link between COPD comorbidity and enhanced PD-1 blockade efficacy. The presence of this tumor-macrophage axis in patients with NSCLC with favorable immunotherapy outcomes highlights its translational potential as both a predictive biomarker and a therapeutic target to improve checkpoint blockade responsiveness.
This work was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0529403) and the National Natural Science Foundation of China (82370028, 82422001, 32330061, and 82303972).
Authors
Chen Chen, Ye Ye, Liu Liu, Li Li, Sun Sun, Jin Jin, Tang Tang, Tang Tang, Fang Fang, Shao Shao, Yao Yao, Chang Chang, Gu Gu, Zhu Zhu, Chen Chen, Shao Shao, Jiang Jiang, Hu Hu, Zhang Zhang, Zhong Zhong, Qiu Qiu, Guo Guo, Xia Xia, Fan Fan
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