Abnormal epigenetic patterns correlate with effector T cell malfunction in tumors 1 – 4 . However, their causal link is unknown. Here, we show that tumor cells disrupt methionine metabolism in CD8 + T cells, thereby lowering intracellular methionine levels and the methyl donor S-adenosylmethionine (SAM), resulting in loss of H3K79me2. Consequently, loss of H3K79me2 led to low STAT5 expression and impaired T cell immunity. Mechanistically, tumor cells avidly consumed and outcompeted T cells for methionine via high expression of SLC43A2, a methionine transporter. Genetic and biochemical inhibition of tumor SLC43A2 rescued T cell H3K79me2 levels, boosting spontaneous and checkpoint-induced tumor immunity. Moreover, we found that methionine supplementation improved expression of H3K79me2 and STAT5 in T cells, accompanied by increased T cell immunity in tumor bearing models and colon cancer patients. Clinically, tumor SLC43A2 negatively correlated with T cell histone methylation and functional gene signatures. Our work reveals a novel mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumor microenvironment. Thus, cancer methionine consumption is an unappreciated immune evasion mechanism, and targeting cancer methionine signaling may provide an immunotherapeutic approach.

Fucoidan is a natural derived compound found in different species of brown algae and in some animals, that has gained attention for its anticancer properties. However, the exact mechanism of action is currently unknown. Therefore, this review will address fucoidans structure, the bioavailability, and all known different pathways affected by fucoidan, in order to formulate fucoidans structure and activity in relation to its anti-cancer mechanisms. The general bioactivity of fucoidan is difficult to establish due to factors like species-related structural diversity, growth conditions, and the extraction method. The main pathways influenced by fucoidan are the PI3K/AKT, the MAPK pathway, and the caspase pathway. PTEN seems to be important in the fucoidan-mediated effect on the AKT pathway. Furthermore, the interaction with VEGF, BMP, TGF-β, and estrogen receptors are discussed. Also, fucoidan as an adjunct seems to have beneficial effects, for both the enhanced effectiveness of chemotherapy and reduced toxicity in healthy cells. In conclusion, the multipotent character of fucoidan is promising in future anti-cancer treatment. However, there is a need for more specified studies of the structure–activity relationship of fucoidan from the most promising seaweed species.

Tissue-resident memory T cells (TRM) represent a heterogeneous T cell population with the functionality of both effector and memory T cells. TRM express residence gene signatures. This feature allows them to traffic to, reside in, and potentially patrol peripheral tissues, thereby enforcing an efficient long-term immune-protective role. Recent studies have revealed TRM involvement in tumor immune responses. TRM tumor infiltration correlates with enhanced response to current immunotherapy and is often associated with favorable clinical outcome in patients with cancer. Thus, targeting TRM may lead to enhanced cancer immunotherapy efficacy. Here, we review and discuss recent advances on the nature of TRM in the context of tumor immunity and immunotherapy.

Histone deacetylase inhibitors (HDIs) are a group of potent epigenetic drugs which have been investigated for their therapeutic potential in various clinical disorders, including hematological malignancies and solid tumors. Currently, several HDIs are already in clinical use and many more are on clinical trials. HDIs have shown efficacy to inhibit initiation and progression of cancer cells. Nevertheless, both pro-invasive and anti-invasive activities of HDIs have been reported, questioning their impact in carcinogenesis. The aim of this review is to compile and discuss the most recent findings on the effect of HDIs on the epithelial-mesenchymal transition (EMT) process in human cancers. We have summarized the impact of HDIs on epithelial (E-cadherin, β-catenin) and mesenchymal (N-cadherin, vimentin) markers, EMT activators (TWIST, SNAIL, SLUG, SMAD, ZEB), as well as morphology, migration and invasion potential of cancer cells. We further discuss the use of HDIs as monotherapy or in combination with existing or novel anti-neoplastic drugs in relation to changes in EMT.