Background: Mitochondrial calcium uniporter (MCU) complex has been reported to be associated with the tumor occurrence and development in varieties of malignancies. However, the role of MCU complex in colon adenocarcinoma (COAD) remains unclear. Therefore, we constructed a risk score signature based on the MCU complex members to predict the prognosis and response to immunotherapy for patients with COAD. Methods: The MCU complex-associated risk signature (MCUrisk) was constructed based on the expressions of MCU, MCUb, MCUR1, SMDT1, MICU1, MICU2, and MICU3 in COAD. The immune score, stromal score, tumor purity and estimate score were calculated by the ESTIMATE algorithm. We systematically evaluated the relationship among the MCUrisk, mutation signature, immune cell infiltration, and immune checkpoint molecules. The response to immunotherapy was quantified by the Tumor Immune Dysfunction and Exclusion (TIDE). Results: Our results showed that high score of MCUrisk was a worse factor for overall survival (OS) in COAD, and MCUrisk score was significantly higher in advanced COAD. The mutation landscape was different between the MCUrisk-high and MCUrisk-low groups, and the mutation rate of TP53 was remarkably higher in MCUrisk-high group, which strongly suggested TP53 mutation might be associated with mitochondrial calcium dyshomeostasis in COAD. Furthermore, MCUrisk score was negatively correlated with tumor mutation burden (TMB), and combining risk score and TMB as a novel index was better than TMB alone in predicting the prognosis for COAD patients. The compositions of Tregs and M0/M2 macrophages were significantly increased in MCUrisk-high group, whereas CD4⁺ T cells was significantly decreased in MCUrisk-high group. Consistently, the immune score was lower in MCUrisk-high group. The expression levels of immune checkpoint molecules were negatively correlated with the MCUrisk score, including CD58 and CD226. Furthermore, a lower MCUrisk score indicated better response to immunotherapy, and combining risk score and immune score was a novel indicator to precisely predict the response to immuotherapy for COAD patients. Conclusion: Altogether, a novel MCUrisk signature was constructed based on the mitochondrial calcium uptake-associated genes, and a lower MCUrisk score may predict better OS outcome and better response to immunotherapy in COAD.

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