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).