An Immunogenic Cell Death Related Signature Links Efferocytosis to Immunosuppression and Therapeutic Vulnerabilities in DLBCL

DLBCL shows clinical heterogeneity, driven by molecular diversity within the tumor along with diverse components in the tumor microenvironment (TME). Immunogenic cell death (ICD) activates adaptive antitumor immunity by inducing immunogenic signals in cancer cells, positioning it as a key mechanism in tumor immunotherapy. However, the role of ICD in DLBCL pathogenesis remains understood. We analyzed integrated single-cell and bulk RNA-seq data from GEO to identify ICD-related genes via AUCell, ssGSEA, and WGCNA. We constructed an ICD-related signature (ICDRS) via the Mime1 package and validated it in four independent cohorts. Prognostic utility was evaluated via Kaplan‒Meier survival analysis, time-dependent receiver operating characteristic (ROC) curves, and multivariate Cox regression. The TME is characterized by ESTIMATE, CIBERSORT, and ImmuCC. Finally, a combination therapy was designed on the basis of risk stratification and validated in DLBCL models. Integration of single-cell and bulk RNA-seq data identified 122 ICD-related genes, enabling the construction of an ICDRS. The ICDRS demonstrated prognostic value in DLBCL patients. The ICDRS score was an independent predictor of OS in all cohorts and was correlated with clinical indicators, including the IPI, ECOG, and Ann Arbor stage. Importantly, the ICDRS characterized an immunosuppressive microenvironment in high-risk patients and predicted immunotherapy and chemotherapy responses. In DLBCL models, radiotherapy reduced the risk score, and fludarabine-radiotherapy-anti-PD-1 inhibited tumor progression by reversing radiotherapy-induced immunosuppression. The ICDRS serves as a prognostic biomarker for DLBCL, and the combination therapy overcomes radioresistance, thereby establishing a translatable strategy.