Over the past decade or two, targeting metabolism has been effective in the treatment of many diseases and disorders, particularly cancer. In a metabolism focus issue in Cell Chemical Biology, this Voices piece asks researchers from a range of backgrounds: what are some major challenges and opportunities facing the field in the coming years?

Metabolic competition within the tumor microenvironment (TME) shapes the efficacy of anticancer immunity. In the August 3rd issue of Nature, Guo et al.1 show that glutamine is an intercellular metabolic checkpoint between cancer and immune cells. Targeting glutamine metabolism in the TME is a promising strategy to improve anti-cancer therapy.

Individuals with type 1 diabetes (T1D) have an increased risk of osteoporosis and fracture. In this issue of Cell Chemical Biology, Ji et al.1 show that impaired glucose metabolism in the bone-forming osteoblast drives diabetic osteoporosis in Akita mice, a mouse model of T1D.

MHC-II expression on cancer cells is associated with improved treatment outcome. In this issue, Huang et al.1 report a panel of small molecules that selectively upregulate MHC-II on cancer cells through suppression of fatty acid synthase (FASN), resulting in inhibition of tumor growth. Targeting this link between lipid metabolism and antigen presentation may improve response to immunotherapy.

The report of heightened lipid peroxidation has shone a spotlight on vulnerabilities within challenging cancers. In this context, FSP1 emerges as a pivotal regulator, actively countering the destructive effects of lipid peroxidation. In a groundbreaking development detailed in the latest issue of Cell Chemical Biology, Hendricks et al. unveil FSEN1, a potent inhibitor of FSP1. The discovery of FSEN1

T cells play a key role in driving autoimmunity, with alterations in metabolism powering their effector function. In the July 11 issue of Cell Metabolism, Jenkins et al.1 describe how a type 2 diabetes drug, canagliflozin, can be repurposed for the treatment of autoimmune disorders through metabolic reprogramming of the T cell response.

In this issue of Cell Chemical Biology, Bush et al.1 report an in vitro selection method for optimizing CRISPR-Cas9 single-guide RNAs. This approach may be useful in targeting previously intractable genomic sequences. The results also provide insights into which positions in single-guide RNAs are most amenable to modification.

The emergence of antibody based surrogate WNT molecules has revolutionized research exploiting organoid cultures. In this issue of Cell Chemical Biology, Post et al.1 present a refined collection of WNT mimetics with unprecedented WNT/β-catenin pathway activating characteristics. These mimetics hold significant promise for future therapeutic advancements.

Circular RNAs (circRNAs) are covalently closed RNA molecules whose functions are still largely uncharacterized. In the July issue of Cancer Cell, Conn et al.1 demonstrate that circRNA can bind cognate DNA loci, forming circRNA-DNA hybrids (circR loops), driving genetic rearrangements of MLL/KMT2A, which are associated with the most aggressive acute leukemias.

In this issue of Cell Chemical Biology, Liu et al.1 identify TRIM21-mediated ubiquitination of the Hippo pathway kinase MST2, promoting its dimerization and activation. The antidepressant Vilazodone was found to bind to TRIM21, enhancing its activity toward MST2, increasing Hippo activation, and reducing colorectal cancer metastasis.

In this issue, McConnell et al.10 demonstrate that COVID-19 convalescent plasma (CCP)-derived antibodies can neutralize SARS-CoV-2 by proteolytically cleaving the spike protein. The CCP antibody-mediated catalysis has broader implications beyond COVID-19 and can be applicable in understanding the mechanism of antibody-based neutralization of different pathogens.

Immunosuppression contributes to tumor-radiotherapy failure, but the mechanism remains elusive. Wang et al.1 reported that ionizing radiation (IR) induces YTHDF2 expression in myeloid-derived suppressor cells (MDSCs) via an IR-YTHDF2-NF-κB circuit, which contributes to MDSC expansion/migration and treatment failure. Genetic depletion or pharmacological inhibition of YTHDF2 overcomes immunosuppression

Elevated bloodstream levels of uric acid, a mammalian purine degradation product, are associated with several noncommunicable diseases. Recent studies by Kasahara et al. and Liu et al. define purine-degrading activities of the gut microbiota that lower bloodstream uric acid in atherosclerosis and gout disease models, establishing a novel microbial role in host health.

Intestinal fibrosis, often caused by inflammatory bowel disease, can lead to intestinal stenosis and obstruction, but there are no approved treatments. Drug discovery has been hindered by the lack of screenable cellular phenotypes. To address this, we used a scalable image-based morphology assay called Cell Painting, augmented with machine learning algorithms, to identify small molecules that could