OLR1 as a Key Inflammatory Regulator Associated with Poor Response to Neoadjuvant Immunochemotherapy in Resectable Lung Cancer

Xinxin Chen,1,* Siang Zhang,1,* Xuefeng Ai,2,* Yongfei Fan,2 Wenjie Chen11Department of Thoracic Surgery, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Military Medical University, Shanghai, People’s Republic of China; 2Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wenjie Chen, Department of Thoracic Surgery, Shanghai Changzheng Hospital, Second Affiliated Hospital of Naval Medical University, No. 415 Fengyang Road, Huangpu District, Shanghai, 200003, People’s Republic of China, Email drchenwenjie@163.com Yongfei Fan, Department of Thoracic Surgery, Shanghai Pulmonary Hospital, No. 507, Zhengmin Road, Shanghai, 200433, People’s Republic of China, Email fanyongfei_fahustc@163.comBackground: Poor pathological response to neoadjuvant immunotherapy combined with chemotherapy (nICT) limits long-term survival in resectable lung cancer. How to improve response rates and the regulatory mechanism of tumor inflammatory signaling in nICT efficacy remain unclear.Methods: In this study, patients were stratified into molecular subgroups using unsupervised consensus clustering based on inflammatory response genes (IRGs) expression profiles. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were applied to characterize tumor inflammatory states, immune microenvironment heterogeneity, and spatial organization between major pathological response (MPR) and non-MPR (NMPR) patients. Differentially expressed gene (DEG) analysis was performed to identify potential therapeutic targets, followed by preliminary functional validation to explore their biological roles.Results: Consensus clustering identified four molecular subgroups with distinct survival outcomes and clinical characteristics. scRNA-seq profiling uncovered that intratumoral inflammatory activation was markedly elevated in NMPR patients relative to MPR patients, with neutrophil subsets exhibiting the most robust inflammatory response among all immune cell populations. Further subset analysis identified two pro-inflammatory neutrophil populations (N3_CXCL8 and N4_VCAN), which were enriched in hypoxic tumor regions and contributed to immune evasion and angiogenesis. OLR1 was identified as a key regulatory hub associated with inflammatory activation, immunosuppression, and pro-angiogenic signaling. In addition, OLR1+ monocytes and macrophages exhibited consistent pro-tumor inflammatory phenotypes.Conclusion: This study identifies an OLR1-associated inflammatory regulatory axis that contributes to impaired response to nICT in lung cancer. Targeting OLR1 may represent a promising strategy to enhance immunotherapy efficacy and improve clinical outcomes in patients with resectable lung cancer. However, the study is limited by a relatively small validation cohort and a strong reliance on bioinformatics analyses, underscoring the need for further translational research and clinical validation to facilitate potential therapeutic application.Keywords: tumor-associated inflammation, OLR1, immune escape, pathological angiogenesis, immunotherapy