Research articles

De Palma and colleagues develop a dendritic cell therapy based on dendritic cell progenitors engineered to produce IL-12 and FLT3L and show antigen-agnostic reduction of tumor burden that can be exploited for combination therapy in glioma.

Palmer and colleagues present a computational model of drug additivity that can predict clinical efficacy for the majority of combination therapy trials in advanced cancer that led to US Food and Drug Administration approvals between 1995–2020.

Using whole-genome and single-cell RNA sequencing data of patients with multiple myeloma treated with carfilzomib, lenalidomide, dexamethasone and daratumumab, Maura et al. identify distinct genomic drivers and microenvironment changes affecting outcome.

Bruedigam et al. explore the mechanism of action and therapeutic benefit of telomerase inhibitor imetelstat in a collection of PDXs from patients with AML and demonstrate that, in combination with chemotherapy, it re-sensitizes treatment-resistant AML cells.

Wiita and colleagues use cross-linking mass spectrometry and glycoprotein surface capture to identify an activated conformation of integrin β₂ present on AML cells and develop CAR T cells that target this conformation antigen in preclinical models.

Abdel-Wahab and colleagues perform immunophenotyping of AML cells to identify AML-specific surface antigens and show that the RNA helicase U5 snRNP200 represents a therapeutic target for antibody therapy with optimized Fc receptor binding.

Feng et al. describe a gasdermin D circRNA-based approach to target mitochondrial inner membrane cardiolipin and demonstrate that this tool can trigger mitochondrial autophagy and affect tumor growth and immunity in EIF4G2⁺ /PTBP1⁺ pan-adenocarcinoma.

Recouvreux et al. show that inhibiting glutamine metabolism in pancreatic cancer blocks tumor growth and that therapy effectiveness is linked to asparagine metabolism, which can be synergistically targeted.

Kimmelman and colleagues show that inhibition of glutamine (Gln) metabolism using a Gln antagonist decreases pancreatic cancer tumor growth, but is compensated by upregulation of extracellular signal-regulated kinase signaling, which can be co-targeted.

Hart et al. study the transmissible marine leukemia of the soft-shell clam Mya arenaria and focus on a cancer lineage that is characterized by varied genomic instability as well as a mutational signature that includes an error-prone polymerase.

Bruzos et al. analyze >6,800 samples of Cerastoderma edule, generate a reference genome and follow the evolution of bivalve transmissible neoplasia that infects them. They find two lineages that show genomic instability but also long-term tolerance.

Olweus and colleagues identify a T cell receptor reactive against the recurrent D835Y driver mutation in FLT3 in acute myeloid leukemia and show that engineered T cells against this neoantigen provide efficient immunotherapy.

Liebers and colleagues present a prospective non-interventional trial in 80 individuals with hematologic cancer investigating the potential of ex vivo drug response profiling and show it to be clinically feasible.

Taylor et al. show that tumor cells promote white adipose tissue (WAT) wasting and cachexia by overactivation of Notch1 signaling and retinoic acid production in distant WAT endothelium, which can be therapeutically targeted to inhibit wasting.

Coukos and colleagues conduct a phase 1 study to evaluate the benefit of adoptive transfer of ex vivo-expanded, vaccine-primed T cells in patients with ovarian cancer—a cancer type that often does not respond to immune checkpoint blockade.

Miyazaki et al. characterize vepafestinib, a next-generation RET inhibitor that is selective for wild-type RET and solvent front mutants. Due to a unique binding mode, it has enhanced brain penetrance and overcomes resistance to other RET inhibitors.

Miller et al. show that blocking ACSS2 remodels acetate metabolism in cancer cells, thereby freeing acetate for tumor-infiltrating lymphocytes, which bolsters their effector function and promotes antitumor immunity in breast cancer.

Wartewig et al. show that PDCD1 in T cell lymphoma restricts glycolytic energy and acetyl-CoA production. Inhibition of PD-1 signaling enforces ACLY activity and generates extramitochondrial acetyl-CoA for histone acetylation to enable AP-1 hyperactivation.

Huang and colleagues identify that EAG2 and Kvβ2 physically interact to form a potassium channel complex in glioblastoma and develop a designer peptide that disrupts their interaction and induces tumor regression.

Zhou et al. investigate the molecular events that follow neoadjuvant treatment in PDAC patients, explore signatures of heterogeneous response and persister phenotypes, identify a CYP3A link to resistance and suggest that it is useful in predicting response.