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Lung cancer has been shown to be targetable by novel immunotherapies which reactivate the immune system and enable tumor cell killing. However, only few patients respond to this promising approach that has the potential to cure even metastatic disease. We hypothesize that the success of the treatment is impaired by the presence of immunosuppressors in the tumor microenvironment and therefore investigated the role of the immunosuppressive glycoprotein glycodelin that is expressed in patients with non-small-cell lung cancer (NSCLC). We demonstrate that the glycan pattern of NSCLC-derived glycodelin detected by a lectin-based enrichment assay highly resembles amniotic fluid-derived glycodelin A, which is known to have immunosuppressive properties. Binding assays with different leucocyte cell lines and subsequent transcriptome analyses reveal that glycodelin indeed interacts with immune cellsin vitroand regulates the expression of genes associated with inflammatory and tumor microenvironment pathways. Furthermore, multiplex immunofluorescence staining of glycodelin and different leucocytes in tumor microarray samples of patients with NSCLC show that glycodelin binds to tumor infiltrating CD8+ T cells and pro-tumorigenic M2 macrophages. Interestingly, we observe that high serum concentrations of glycodelin prior to immunotherapy are associated with a poor progression-free survival (p < 0.001) of female patients receiving PD-(L)1 inhibitors. Our findings demonstrate that glycodelin not only is a promising immunological biomarker for early identification of female patients that do not benefit from the costly immunotherapy, but also represents a promising immunotherapeutic target in NSCLC to improve therapeutic options in lung cancer.