Predictive value of an ICD-associated DAMP gene signature for survival and immunotherapy response in osteosarcoma patients.

BACKGROUND

The tumor microenvironment (TME) in osteosarcoma, shaped by damage-associated molecular patterns (DAMPs) released during immunogenic cell death (ICD)-a process that elicits robust immune responses-critically modulates antitumor immunity, particularly in this aggressive malignancy. Despite the recognized importance of DAMPs in various cancers, including osteosarcoma, comprehensive research into their impact specifically within osteosarcoma remains limited. This study aims to elucidate the impact of DAMPs on immune cell infiltration and antitumor immunity in osteosarcoma by identifying and characterizing DAMP-associated gene expression profiles.

METHODS

This study analyzed a curated set of ICD-related DAMP genes from the TARGET-OS and GSE21257 datasets to investigate their prognostic significance in osteosarcoma patients. We applied unsupervised clustering to classify osteosarcoma patients into distinct DAMP-associated subtypes based on gene expression profiles. The gene expression profiles and their prognostic significance were evaluated using univariate and multivariate Cox regression analyses in the osteosarcoma cohort. Immune characteristics were assessed using the ESTIMATE and ssGSEA algorithms, with molecular differences compared between the subtypes. GO and KEGG enrichment analyses were performed to identify immune-related biological pathways underlying the DAMP-associated subtypes.

RESULTS

Two DAMP-associated subtypes with distinct prognostic profiles were identified; Cluster 1 exhibited poorer survival outcomes and elevated expression of immune checkpoint molecules, indicative of an immunosuppressive tumor microenvironment. A prognostic model, constructed using LASSO-selected genes (FPR1, TLR4), effectively stratified patients into high- and low-risk groups, with the low-risk group demonstrating superior survival and potential responsiveness to immunotherapy.

CONCLUSION

Our findings underscore the critical role of DAMP-related genes in influencing the immune landscape of osteosarcoma, providing novel insights into the mechanisms that drive differential responses to treatment. By harnessing the prognostic potential of DAMP-related genes, this study advances personalized medicine in osteosarcoma, potentially improving the efficacy of immunotherapeutic interventions.