Single-Cell RNA Sequencing Reveals Immunosuppressive Mechanisms of MDSCs in Lung Cancer

School of Biomedical Engineering, University of Technology Sydney, Sydney 2000, Australia

^* Corresponding author: 2595198998@qq.com

Abstract

Lung cancer remains one of the leading causes of cancer-related mortality, with a five-year survival rate of approximately 9% following metastasis. The tumor microenvironment (TME) is highly immunosuppressive, facilitating immune evasion and tumor progression. Myeloid-derived suppressor cells (MDSCs) play a key role in this process by upregulating immunosuppressive genes such as ARG1, iNOS, and PD-L1. In this study, we analyzed tumor tissue samples from 200 lung cancer patients, including both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cases, using single-cell RNA sequencing (scRNA-seq) to characterize MDSC-associated gene expression. Demographic and clinical data were considered to enhance the generalizability of findings. Results showed that ARG1 overexpression depleted arginine, inhibiting T cell proliferation, while iNOS upregulation induced oxidative stress and impaired T cell receptor signaling. PD-L1 overexpression suppressed anti-tumor immunity through checkpoint inhibition. Pathway enrichment analysis indicated that these mechanisms act synergistically to drive tumor progression. While these findings highlight ARG1, iNOS, and PD-L1 as promising therapeutic targets for overcoming MDSC-mediated immunosuppression, potential challenges remain, including off- target effects and resistance mechanisms that may limit clinical efficacy. Addressing these pathways could enhance immunotherapy and mitigate drug resistance. This study provides a foundation for developing combination therapies targeting MDSCs to improve lung cancer prognosis.