Derlin-3 has been implicated as an essential element in the degradation of misfolded lumenal glycoproteins induced by endoplasmic reticulum (ER) stress. However, its potential biomechanisms in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD) remains to be elucidated. 

Clinical samples were used to investigate the differential expression of Derlin-3 in LUAD and its association with prognosis. Single-cell RNA sequencing (scRNA-seq) was employed to analyze the enrichment of Derlin-3 in LUAD cell subclusters and its link to ER stress. Magnetic bead sorting combined with tissue immunofluorescence and transmission electron microscopy were utilized to explore Derlin-3's role in ER stress. Identifying differentially expressed genes in Derlin-3+/− plasma cell subclusters and performed pathway enrichment analysis to elucidate the mechanisms of Derlin-3 involvement in ER stress using scRNA-seq. The mechanisms of Derlin-3-regulated IgG4 secretion in the polarization of M2 macrophages were conducted via Western blotting and flow cytometry. In vivo experiments, urethane-induced and Derlin-3-silenced LUAD models were used to explored Derlin-3's role in LUAD development.

It was found that Derlin-3 was predominantly elevated in LUAD tissues, and could predict worse prognosis of LUAD patients. ScRNA-seq analysis indicated that Derlin-3 was mainly enriched in B lymphocytes in the TME, especially in plasma cells. Moreover, Derlin-3 may be involved in ER stress and IgG4 secretion in plasma cells by targeting p38/PRDM1 pathway. While the aberrant IgG4 production may be an essential driver of the polarization of macrophages towards the M2 phenotype. Additionally, downregulation of Derlin-3 could inhibit plasma cells infiltration and M2 macrophage polarization in vivo.

In summary, we demonstrated that Derlin-3 was mainly enriched in plasma cells in TME. The p38/PRDM1 signaling was involved in IgG4 secretion and might promote macrophage M2 polarization. These findings indicate a promising discovery of potential prognostic predictors and immunotherapeutic strategies for LUAD.