Metabolic rewiring of cancer cells is one of the hallmarks of cancer. As a consequence, the metabolic landscape of the tumour microenvironment (TME) differs compared to correspondent healthy tissues. Indeed, due to the accumulation of acid metabolites, such as lactate, the pH of the TME is generally acidic with a pH drop that can be as low as 5.6. Disruptions in the acid-base balance and elevated lactate levels can drive malignant progression not only through cell-intrinsic mechanisms but also by impacting the immune response. Generally, acidity and lactate dampen the anti-tumour response of both innate and adaptive immune cells favouring tumour progression and reducing the response to immunotherapy. In this review, we summarize the current knowledge on the functional, metabolic and epigenetic effects of acidity and lactate on the cells of the immune system. In particular, we focus on the role of monocarboxylate transporters (MCTs) and other solute carrier transporters (SLCs) that, by mediating the exchange of lactate (among other metabolites) and bicarbonate, participate in pH regulation and lactate transport in the cancer context. Finally, we discuss advanced approaches to target pH or lactate in the TME to enhance the anti-tumour immune response.

The metabolism of cancer cells is generally very different from what is found in normal counterparts. However, in a tumor mass, the continuous crosstalk and competition for nutrients and oxygen among different cells lead to metabolic alterations, not only in cancer cells, but also in the different stromal and immune cells of the tumor microenvironment (TME), which are highly relevant for tumor progression. MicroRNAs (miRs) are small non-coding RNAs that silence their mRNA targets post-transcriptionally and are involved in numerous physiological cell functions as well as in the adaptation to stress situations. Importantly, miRs can also be released via extracellular vesicles (EVs) and, consequently, take part in the bidirectional communication between tumor and surrounding cells under stress conditions. Certain miRs are abundantly expressed in stromal and immune cells where they can regulate various metabolic pathways by directly suppressing enzymes or transporters as well as by controlling important regulators (such as transcription factors) of metabolic processes. In this review, we discuss how miRs can induce metabolic reprogramming in stromal (fibroblasts and adipocytes) and immune (macrophages and T cells) cells and, in turn, how the biology of the different cells present in the TME is able to change. Finally, we debate the rebound of miR-dependent metabolic alterations on tumor progression and their implications for cancer management.

The progression to critical COVID-19 arises predominantly from a dysregulated host immune response although the underlying regulatory mechanisms still rema