UNC5B Knockdown Enhances Chemotherapy Sensitivity and Immunogenic Cell Death in Sarcoma: A Comprehensive Prognostic Analysis based on PANoptosis and Macrophage

Abstract Purpose Sarcomas represent a heterogeneous collection of malignancies originating from mesodermal tissues, posing significant challenges in diagnosis and treatment. Emerging research has spotlighted PANoptosis—a synergistic process of pyroptosis, apoptosis, and necroptosis—as a novel therapeutic target. This study seeks to construct a prognostic model leveraging PANoptosis and macrophage-related genes to advance the understanding and treatment of sarcoma. Methods Utilizing data from the TCGA-SARC, TARGET-OS cohorts, and GSE159847, we identified genes associated with macrophages and PANoptosis. A prognostic model was formulated through multivariate and LASSO regression analyses, with its efficacy evaluated via Kaplan-Meier survival analysis, ROC curves, and validation with an independent cohort. Comprehensive analyses included functional enrichment, immune microenvironment assessment, and drug response prediction. Additionally, functional assays were performed on 143B cells to elucidate the pivotal gene’s roles. Results The prognostic model, incorporating four genes (CD2, STAT6, TXNIP, UNC5B), effectively categorized samples into high and low risk cohorts with notable survival disparities. Samples from the high-risk group exhibited greater genomic instability and immunosuppressive microenvironments. Functional assays in 143B cells revealed that knockdown of UNC5B reduced cell proliferation and increased sensitivity to paclitaxel, indicating potential therapeutic targets. Conclusion This study highlights the critical role of PANoptosis and macrophage polarization in the sarcoma microenvironment. The prognostic model devised provides a reliable instrument for predicting patient outcomes and tailoring personalized treatment strategies, thereby offering innovative therapeutic pathways for sarcoma management.