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Wu et al. utilize multiparametric analysis of early-stage human NSCLC to characterize a population of Vδ1 T cells displaying a resident memory and effector memory phenotype, which were associated with ongoing remission.
Zhu and colleagues identify GREMLIN1 as an FGFR1 ligand that promotes plasticity and castration resistance in prostate cancer through regulation of MAPK signaling, and show that anti-GREMLIN1 antibody therapy synergizes with androgen deprivation.
Weaver and colleagues use breast cancer patient-derived organoids and mouse models to find an inhibitory role for the nuclear repressor NCOR2 in chemotherapy response and antitumor immunity, which can be targeted by blocking NCOR2–HDAC3 interaction.
Armstrong and colleagues discover that combined targeting of IKAROS and MENIN is a therapeutic strategy for acute myeloid leukemia through disruption of essential leukemogenic transcriptional programs.
Li et al. demonstrate mitochondrial fission in macrophages as key for phagocytosis induced by therapeutic antibodies. They identify overexpression of GFPT2 as an inhibitor of the process and phase transition of the phagocytic machinery as its regulator.
Alborzinia et al. report that MYCN-amplified neuroblastoma undergoes ferroptosis in the absence of intracellular cysteine, suggesting a combination of cysteine depletion and concomitant GPX4 inactivation as a potential therapeutic approach.
Hongu et al. find that perivascular macrophages stimulate activation of the pro-metastatic vascular niche via tenascin C stimulation of TLR4 and show that combined TLR4 and VEGF inhibition prevents TNC-mediated metastatic vascular activity.
Batlle and colleagues develop an organoid platform for functional antibody screening and identify a therapeutic bispecific antibody that binds EGFR and LGR5 and that shows efficacy across epithelial tumor patient-derived xenograft models in vivo.
Ji and colleagues demonstrate that metabolic reprogramming in SCLC underlies chemotherapy resistance, resulting in an actionable dependency on the mevalonate pathway in tumor cells, which can be targeted using statins to revert chemoresistance.
Na et al. identify KMT2C deficiency as a driver of small cell lung cancer metastasis and demonstrate that it leads to epigenetic reprogramming through histone and DNA hypomethylation by upregulating DNMT3A.
Golub and colleagues identify the phosphate exporter XPR1 as a therapeutic vulnerability in ovarian and uterine cancers, and show that phosphate efflux inhibition reduces tumor cell viability through accumulation of intracellular phosphate.
Jänne and colleagues discover and characterize an allosteric EGFR inhibitor with efficacy against therapy-resistant mutations and show preclinical efficacy as monotherapy and in combination in patient-derived xenograft models.
Agnihotri and colleagues show that loss of the MAT2A enzyme of the methionine cycle induces a global depletion of H3K36me3 and extends survival in glioma models, representing a potential therapeutic vulnerability.
Li and colleagues use single-cell techniques to identify features of T cells in the tumor and draining lymph nodes involved in the efficacy of immune checkpoint blockade combined with a neoantigen vaccine in preclinical models.
Lim and colleagues present the UK PROSECO study where they assess humoral and cellular immune responses to one, two and three doses of vaccination against SARS-CoV-2 in patients with B-cell malignancies in a prospective observational study.
Hua and colleagues develop CAR T cells targeting CDH17 and show that they are effective at suppressing tumor growth in mouse and human models of neuroendocrine and gastrointestinal solid tumors, without damaging healthy tissues in preclinical models.
Celià-Terrassa and colleagues identify LCOR-low cancer stem cells driving tumor immunity and propose LCOR induction with mRNA therapy as an enhancer of immunotherapy response.
Alvarez and colleagues develop a bispecific anti-PD-1–GITR-L agonist that activates T cells via a mechanism distinct from those found with individual PD-1 and GITR-L agonists and demonstrate its antitumor activity in mice and nonhuman primates.
Amit and colleagues report that the specific interaction of a CD4+PD-1+CXCL13+ T-cell subset with antigen-presenting cells reprograms the tumor microenvironment and response to immune checkpoint inhibitors in non-small cell lung cancer.
Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.