BACKGROUND: Macrophages are closely associated with the progression of Kidney renal clear cell carcinoma (KIRC) and can influence programmed cell death (PCD) of tumour cells. To identify prognostic biomarkers for KIRC, it is essential to investigate the association between macrophage-related genes and PCD characteristics.

METHODS: Clinical details and transcriptome data from 693 KIRC samples were obtained from multiple databases, including TCGA and GEO. Genes associated with macrophages and programmed cell death (PCD) were identified and key regulatory genes and PCD patterns were analyzed. The relationship between macrophages and 18 types of cell death is under investigation with a powerful computational framework. Ten machine learning algorithms, 101 unique combinations of algorithms were utilized to build a macrophage-associated programmed cell death (MacPCD) model to predict KIRC patient survival. Immunohistochemistry and RT-qPCR were used for genetic analysis of MacPCD models.

RESULTS: The MacPCD model is made up of six genes which showed strong predictive power for the prognosis of patients with KIRC. Immunohistochemistry and RT-qPCR showed that among the MacPCD model genes, BID, SLC25A37 and BNIP3L were highly expressed in tumour tissues, whereas ACSL1, SDHB and ALDH2 were highly expressed in normal tissues. Biologically, the high MacPCD group showed higher tumor mutation burden and increased immune cell infiltration and high expression of immunomodulators. In particular, MacPCD was an independent prognostic indicator of KIRC and was the best predictor of KIRC survival (AUC = 0.920) compared with multiple clinical variables (Age, M, and Stage).

CONCLUSION: We used a powerful machine learning framework to highlight the great potential of MacPCD in providing personalised risk assessment and immunotherapy intervention recommendations for KIRC patients.