Development and validation of a disulfidptosis and M2 TAM-related classifier for bladder cancer to explore tumor subtypes, immune landscape and drug treatment.

Abstract

Disulfidptosis, as a new mode of programmed cell death, is closely associated with tumorigenesis. Meanwhile, M2 tumor-associated macrophage (TAM) plays an important role in tumor progression. Here, we propose to combine these two perspectives to detect novel disulfidptosis and M2 TAM-related biomarkers in bladder cancer (BCa) to identify various tumor subtypes, construct prognostic features, reveal immune and somatic mutational landscapes, and screen for drugs in BCa. We used weighted gene co-expression network analysis (WGCNA) to mine M2 TAM-related genes. Consensus unsupervised clustering was performed to identify potential tumor subtypes. The least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analyses were utilized to build the risk model. We then explored the immune cell, immune function, immune checkpoint expression patterns and somatic mutational landscape in clusters and risk groups. In addition, we performed sensitivity analysis for anti-cancer drugs. We identified 3057 M2 TAM-related genes and intersected them with disulfidptosis-related genes to obtain 95 disulfidptosis and M2 TAM-related genes (DMRGs). In terms of tumor subtypes, two molecular clusters were identified. Cluster 1 showed stronger immunogenicity and higher tumor mutational burden (TMB). We also predicted 50 drugs with high sensitivity in cluster 1. On the basis of risk grouping, the high-risk group had poor overall survival in the training, test, and validation groups. Ten screened anti-cancer drugs were more sensitive in the high-risk group. A nomogram predicting survival of BCa patients was also established. By combining two hotspot perspectives, disulfidptosis and M2 TAM, we provide a valuable risk score signature for establishing individualized treatment regimens and drug choices. The risk score may serve as an independent risk factor for BCa patients.