Ionic reverberation modulates the cellular fate of CD8+tissue resident memory T cells (TRMs) in patients with renal cell carcinoma: A novel mechanism

In metastatic renal cell carcinoma (mRCC), existing treatments including checkpoint inhibitors are failed to cure and/or prevent recurrence of the disease. Therefore, in-depth understanding of tumor tissue resident memory T cells (TRMs) dysfunction are necessitated to enrich efficacy of immunotherapies and increasing disease free survival in treated patients. In patients, we observed dysregulation of K+, Ca2+, Na2+ and Zn2+ ion channels leads to excess infiltration of their respective ions in tumor TRMs, thus ionic gradients are disturbed and cells became hyperpolarized. Moreover, overloaded intramitochondrial calcium caused mitochondrial depolarization and trigger apoptosis of tumor TRMs. Decreased prevalence of activated tumor TRMs reflected our observations. Furthermore, disruptions in ionic concentrations impaired the functional activities and/or suppressed anti-tumor action of circulating and tumor TRMs in RCC. Collectively, these findings revealed novel mechanism behind dysfunctionality of tumor TRMs. Implicating enrichment of activated TRMs within tumor would be beneficial for better management of RCC patients. •Excess Na+ and K+ ions in tumor cells elevates necrosis and hyperkalemic tumor microenvironment, which may limit the function of immune cells.•Discrepancy in regulation of calcium flux within tumor TRMs, may trigger the apoptosis of tumor TRMs.•Additionally, excess zinc inhibited the functionality of memory T cells. Hence survivality of TRMs constrained in tumor tissue of RCC patients.