Enhanced immunotherapy response in lung adenocarcinoma patients with COPD: insights into tumor cells and immune microenvironment characteristics.

BACKGROUND: Lung cancer and chronic obstructive pulmonary disease (COPD) are major global health challenges, and their coexistence in patients presents unique clinical complexities. Interestingly, patients with both lung adenocarcinoma (LUAD) and COPD show reduced responses to conventional chemotherapy and targeted therapies but demonstrate enhanced sensitivity to immunotherapy. METHODS: We investigated this phenomenon using a cohort of 248 LUAD patients undergoing immunotherapy. Single-cell transcriptomic analysis was performed on 187,123 cells from tumor samples, adjacent normal tissues, and peripheral blood mononuclear cells from six treatment-naïve LUAD patients—three with COPD and three without. To further validate these findings, we conducted multiplex fluorescent immunohistochemical (mfIHC) analysis on 34 additional treatment-naïve LUAD patients and analyzed an independent cohort of 65 LUAD patients undergoing immunotherapy. RESULTS: We found that COPD-associated LUAD tumors exhibited distinctive features, including elevated expression of human leukocyte antigen I (HLA-I) on malignant cells and a less aggressive tumor phenotype. The immune microenvironment in these tumors was more active, with increased infiltration of NK cells, effector CD4(+) T cells, and effector CD8(+) T cells. Additionally, we observed higher numbers of exhausted C-X-C motif chemokine ligand 13(+) CD8(+) T cells and mature dendritic cells enriched in immunoregulatory molecules expressing immune checkpoint genes. These findings were confirmed in both the mfIHC cohort and the independent immunotherapy cohort, where we observed that COPD-related features correlated with improved responses to immunotherapy. CONCLUSION: Our study reveals that COPD leads to elevated HLA-I expression and a more active immune microenvironment in LUAD tumors, characterized by enhanced cytotoxic immune cell infiltration and a shift towards immunoregulatory profiles. These features correlate with improved immunotherapy responses, highlighting the potential for optimizing treatment strategies in LUAD patients with COPD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-025-02332-7.