Abstract
BACKGROUND: Ion channels play key regulatory roles in cancer pathophysiology. They are also considered promising therapeutic targets. The transient receptor potential melastatin 4 (TRPM4) is a nonselective monovalent cation channel, recently identified as critical in necrosis by sodium overload. Multiple studies have demonstrated that this gene is a potential player in cancer biology; however, its comprehensive role in various cancer types remains largely unexplored. METHODS: In this study, we conducted a comprehensive bioinformatics analysis of TRPM4 across multiple cancer types, examining its expression patterns, prognostic significance, and clinical relevance. We investigated epigenetic modifications, the DNA damage repair response, as well as alternative splicing and intronic polyadenylation associated with TRPM4. In addition, we analyzed signaling pathways related to tumorigenesis and immune responses, alongside assessing immune cell infiltration in tumor microenvironments. RESULTS: We systematically delineate the expression heterogeneity of TRPM4 across pan-cancer and its clinical implications: it acts as a risk factor indicating poor prognosis in ACC, LGG, PAAD, MESO, and UVM, whereas it exhibits a protective role in KIRP and UCEC. Mechanistically, TRPM4 is involved not only in epigenetic regulation and DNA damage repair responses but also modulates post-transcriptional processes such as alternative splicing and intronic polyadenylation. Furthermore, TRPM4 expression is significantly associated with multiple tumor-related signaling pathways and immunomodulatory molecules. More importantly, through tumor microenvironment infiltration analysis, we observed spatial co-localization of TRPM4 with CD68⁺ tumor-associated macrophages, suggesting that TRPM4 may exert a potential immunomodulatory function by shaping the tumor immune microenvironment through influencing immune cell infiltration. CONCLUSION: Our research highlights TRPM4 as a promising biomarker and a therapeutic target for cancer treatment. Future investigations should focus on elucidating the mechanistic role of TRPM4 in modulating immune response and tumor progression, potentially paving the way for innovative therapeutic strategies in oncology.