Why and how citrate may sensitize malignant tumors to immunotherapy

Immunotherapy, either alone or in combination with chemotherapy, has demonstrated limited efficacy in a variety of solid cancers. Several factors contribute to explaining primary or secondary resistance. Among them, cancer cells, whose metabolism frequently relies on aerobic glycolysis, promote exhaustion of cytotoxic immune cells by diverting the glucose in the tumor microenvironment (TME) to their own profit, while secreting lactic acid that sustains the oxidative metabolism of immunosuppressive cells. Here, we propose to combine current treatment based on the use of immune checkpoint inhibitors (ICIs) with high doses of sodium citrate (SCT) because citrate inhibits cancer cell metabolism (by targeting both glycolysis and oxidative metabolism) and may active anti-tumor immune response. Indeed, as showed in preclinical studies, SCT reduces cancer cell growth, promoting cell death and chemotherapy effectiveness. Furthermore, since the plasma membrane citrate carrier pmCIC is mainly expressed in cancer cells and low or not expressed in immune and non-transformed cells, we argue that the inhibition of cancer cell metabolism by SCT may increase glucose availability in the TME, thus promoting functionality of anti-tumor immune cells. Concomitantly, the decrease in the amount of lactic acid in the TME may reduce the functionality of immunosuppressive cells. Preclinical studies have shown that SCT can enhance the anti-tumor immune response through an enhancement of T cell infiltration and activation, and a repolarization of macrophages towards a TAM1-like phenotype. Therefore, this simple and cheap strategy may have a major impact to increase the efficacy of current immunotherapies in human solid tumors and we encourage testing it in clinical trials.