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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.
Chen and colleagues, using a large multicenter prospective study, show the feasibility and survival benefits of annual screening for hepatocellular carcinoma in individuals at high risk based on hepatitis B surface antigen seropositivity.
Goswami and colleagues identify high expression of KDM6B in immune-suppressive myeloid cells in glioblastoma and show that its myeloid cell-specific deletion enhances inflammatory signaling and antigen presentation, thereby extending survival.
Derrien et al. analyze three patients relapsing on talquetamab, a bispecific antibody against CD3 and GPRC5D, and show that acquired resistance is mediated by genetic inactivation or by long-range epigenetic silencing of GPRCD5.
Cox and colleagues develop PXS-5505, a first-in-class selective pan-lysyl oxidase inhibitor and show that it reduces chemotherapy-induced desmoplasia and stiffness, thereby improving chemotherapy response and survival in pancreatic cancer models.
Zheng et al. show that ChAT-expressing cholinergic T cells suppress the development of liver cancer via their cholinergic activity, which constrains calcium/NFAT signaling induced by TCR engagement.
Grockowiak et al. explore bone marrow niche heterogeneity in myeloproliferative neoplasms, polycytemia vera and essential thrombocytemia and find JAK2-mutated hematopoietic stem cells occupying distinct niches affecting cell growth and therapy response.
Wu et al. show that versions of IL-2 that preserve CD25 activity expand tumor-specific T cells more effectively than CD25-sparing agonists and find that the efficacy of anti-PD-1 depends on the activation of PD-1+CD25+ T cells through autocrine IL-2 signaling.
Wang and colleagues generate two protein-level mutant p53 reporters and use them to identify precancerous clones in normal tissues in vivo, characterized by increased amino acid metabolism and a transcriptomic signature that includes Ybx3.
Guccione and colleagues identify and characterize a sorafenib derivative, WNTinib, with therapeutic efficacy in β-catenin-mutated hepatocellular carcinoma and identify EZH2 as important for the activity of the inhibitor.
Fecci and colleagues show that tumor cells having lost MHC-I, a major mechanism of immune escape, are amenable to killing by CD8+ T cells through an MHC-I-independent, alternative pathway via NKG2D and NKG2DL interaction and granzyme.
Roesch and colleagues use clinical datasets and mouse models of BRAF-mutant melanoma to reveal a role for IL-17A in positive responses to anti-PD-1 and anti-CTLA-4 therapy, which they also link to infiltrating neutrophils.
Wang and colleagues perform single-cell profiling of human ovarian cancer samples from five anatomic sites, revealing dynamics of the immune microenvironment in malignant ascites and cell subtypes that may play a role in chemotherapy response.
Coorens et. al. perform whole-genome sequencing and phylogenetic analyses in a child patient with leukemia that underwent lineage switch following therapy, finding that the AML arose from a pre-existing clone, rather than the most recent ALL relapse.
Lynch and colleagues characterize γδ T cells in colorectal and endometrial cancer and identify distinct subsets with opposing cytotoxic and wound healing functions, leading them to develop an expansion method that enhances cytotoxic functions.