Volume 5 Issue 4, April 2024

Sarcomas are heterogeneous connective tissue tumors that occur at various anatomic sites and are generally difficult to treat. Cell states in sarcoma ecosystems are now shown to be conserved across multiple subtypes and associated with response to immunotherapy and patient outcome.

Arginine methylation is crucial for tumor maintenance. PRMT9 levels are elevated in acute myeloid leukemia, and its inhibition eradicates leukemia by diminishing arginine methylation of proteins involved in DNA damage response and RNA translation. This activates the cGAS–STING pathway, which triggers immune responses directed against leukemia. Epigenetic targeting of DNA-damage-response mechanisms may bolster anti-tumor immunity.

Our study reveals that the LGR4–Wnt signaling pathway dictates both ferroptosis and stemness traits to confer drug resistance to tumor cells. We thus generated a monoclonal antibody against LGR4 that blocks LGR4–Wnt signaling and sensitizes chemotherapy-resistant colorectal cancer tumors via selective promotion of ferroptosis.

Mitochondrial DNA mutations are present in over 50% of all cancers, and truncating mutations in several genes encoding components of complex I of the respiratory chain are most recurrent. We found that these mutations are a source of Warburg-like metabolic shifts that promote a pro-inflammatory immunological state, enhancing sensitivity to checkpoint blockade.

Barker and colleagues discuss the interplay between circadian rhythm, the tumor microenvironment and stem cells and how these are linked to metastasis as well as how these interactions could be clinically relevant.

Suijkerbuijk et al. summarize the clinical manifestation and classification of immune-related adverse events, discuss the immunopathogenesis of immune-related adverse events and provide key insights into their management and future therapeutic directions.

Zheng et al. generate and utilize a biobank of colorectal cancer PDOs to find that high LGR4 is linked to chemoresistance. They develop a monoclonal antibody against LGR4 that activates ferroptosis and is therapeutically beneficial.

De Blank and colleagues examine data from childhood cancer survivors diagnosed between 1970 and 1999 and find that exposure to radiation decreased over time, and radiation was associated with a higher risk of late mortality and subsequent neoplasms.

Dong et al. demonstrate that targeting arginine N-methyltransferase 9 (PRMT9) inhibits cancer stem cells in the context of acute myeloid leukemia via type I interferon-associated immunity. Furthermore, they show that PRMT9 inhibition synergizes with anti-programmed cell death protein 1.

Roland et al. report the results of a randomized, non-comparative phase 2 trial of neoadjuvant nivolumab or a combination of nivolumab and ipilimumab in patients with resectable retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma.

Subramanian et al. use the EcoTyper machine-learning framework to characterize the tumor, immune and stromal cell states and ecosystems that comprise sarcomas.

Gammage and colleagues find that mitochondrial DNA mutations induce alterations in redox metabolism, a remodeled tumor microenvironment characterized by a loss of neutrophils and consequently enhanced responses to immunotherapy in melanoma.

Shao and colleagues present a multiomic analysis of breast tumor samples from Chinese patients, consisting of genomic, transcriptomic, proteomic, metabolomic, radiomic and digital pathology data.