A palmitoylation-related signature predicts prognosis and immune microenvironment features in diffuse large B-cell lymphoma.

BACKGROUND

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma and remains highly heterogeneous in prognosis. Palmitoylation, an important post-translational modification, has been implicated in tumor biology, but its role in DLBCL, particularly in relation to the immune microenvironment, remains unclear.

METHODS

Transcriptomic and clinical data from 706 patients with DLBCL were obtained from the Gene Expression Omnibus database. Prognosis-associated palmitoylation-related genes were identified by differential expression and univariate Cox regression analyses. An optimal prognostic model was developed by comparing 101 machine learning algorithm combinations and was further integrated with clinical variables to construct a nomogram. The tumor immune microenvironment was evaluated using immune infiltration, immune function, immune checkpoint, and Tumor Immune Dysfunction and Exclusion analyses. Weighted gene co-expression network analysis (WGCNA) and Mendelian randomization (MR) were performed to identify key genes, followed by experimental validation.

RESULTS

A 33-gene palmitoylation-related signature (PRS) was established and evaluated across multiple cohorts. PRS was an independent prognostic factor of DLBCL and showed consistent prognostic performance across datasets. Low-risk patients showed higher immune cell infiltration and more active immune function, whereas high-risk patients showed a greater predicted potential to respond to immune checkpoint inhibitor therapy. A nomogram integrating PRS with clinical characteristics also showed favorable predictive accuracy. In addition, two palmitoylation-related molecular subtypes with distinct transcriptomic features, survival outcomes, and immune microenvironment characteristics were identified in DLBCL. CEACAM3 was prioritized as a key candidate gene based on integrated WGCNA and MR analyses, and functional experiments showed that CEACAM3 knockdown suppressed proliferation and invasion and promoted apoptosis, whereas CEACAM3 overexpression enhanced proliferation and invasion, reduced apoptosis, and promoted tumor growth.

CONCLUSION

The PRS captures prognostic heterogeneity and distinct immune microenvironment features in DLBCL. PRS may provide a useful tool for risk stratification, and CEACAM3 may serve as a potential biomarker and therapeutic target in DLBCL.