COPD reshapes the tumor microenvironment of NSCLC and enhances anti-PD-1 therapy response

Med. 2026 Apr 10;7(4):100996. doi: 10.1016/j.medj.2025.100996. Epub 2026 Feb 13.

Abstract

Background: 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.

Methods: 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.

Findings: 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.

Conclusions: 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.

Funding: 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).

Keywords: COPD; CXCL14; NSCLC; anti-PD-1 therapy; immunotherapy efficacy; translation to patients; tumor microenvironment.

MeSH terms

  • Aged
  • Carcinoma, Non-Small-Cell Lung* / complications
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / immunology
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Chemokine CXCL9 / metabolism
  • Female
  • Humans
  • Immune Checkpoint Inhibitors* / therapeutic use
  • Lung Neoplasms* / complications
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / pathology
  • Male
  • Programmed Cell Death 1 Receptor* / antagonists & inhibitors
  • Pulmonary Disease, Chronic Obstructive* / complications
  • Pulmonary Disease, Chronic Obstructive* / immunology
  • Receptors, CXCR4 / metabolism
  • Tumor Microenvironment* / immunology

Substances

  • Immune Checkpoint Inhibitors
  • Programmed Cell Death 1 Receptor
  • Receptors, CXCR4
  • Chemokine CXCL9
  • CXCR4 protein, human