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

Abstract

Background: 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.