Targeting metabolism to improve CAR-T cells therapeutic efficacy

Chimeric antigen receptor T(CAR-T)cell therapy achieved advanced progress in the treatment of hematological tumors.However,the application of CAR-T cell therapy for solid tumors still faces many challenges.Competition with tumor cells for metabolic resources in an already nutrient-poor tumor microenvironment is a major contributing cause to CAR-T cell therapy’s low effectiveness.Abnormal metabolic processes are now acknowledged to shape the tumor microenvironment,which is characterized by increased interstitial fluid pressure,low pH level,hypoxia,accumulation of immunosuppressive metabolites,and mitochondrial dysfunction.These factors are important contributors to restriction of T cell proliferation,cytokine release,and suppression of tumor cell-killing ability.This review provides an overview of how different metabolites regulate T cell activity,analyzes the current dilemmas,and proposes key strategies to reestablish the CAR-T cell therapy’s effectiveness through targeting metabolism,with the aim of providing new strategies to surmount the obstacle in the way of solid tumor CAR-T cell treatment.

Revealing the roles of TLR7, a nucleic acid sensor for COVID-19 in pan-cancer

Recent studies suggested that cancer was a risk factor for coronavirus disease 2019 (COVID-19). Toll-like receptor 7 (TLR7), a severe acute respiratory syndrome 2 (SARS-CoV-2) virus’’s nucleic acid sensor, was discovered to be aberrantly expressed in many types of cancers. However, its expression pattern across cancers and association with COVID-19 has not been systematically studied. In this study, we proposed a computational framework to comprehensively study the roles of TLR7 in COVID-19 and pan-cancers at genetic, gene expression, protein, epigenetic, and single-cell levels. We found TLR7 mRNA expression was significantly up-regulated in 6 cancer types and down-regulated in 6 cancer types, further validated in the HPA database at the protein level. The genes significantly co-expressed with TLR7 were mainly enriched in the toll-like receptor signaling pathway, endolysosome, and signaling pattern recognition receptor activity. In addition, the abnormal TLR7 expression was associated with Mismatch repair (MMR), microsatellite instability (MSI), tumor mutational burden (TMB) in various cancers. Mined by the ESTIMATE algorithm, the expression of TLR7 was also closely linked to various immune infiltration patterns in pan-cancer, and TLR7 was mainly enriched in macrophages, as revealed by single-cell RNA sequencing. Finally, TLR7 expressions were very sensitive to a few targeted drugs, such as Alectinib and Imiquimod. In conclusion, TLR7 might be essential in the pathogenesis of COVID-19 and cancers.