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Izar and colleagues demonstrate that loss of Pip4k2c in melanoma cells promotes liver metastatic tropism driven by PI3K-AKT pathway activation in the insulin-rich liver milieu, which can be abrogated by inhibition of SGLT2 or a ketogenic diet.
Chaib et al. find that therapy-induced senescent cells have high programmed cell death 1 ligand 2 (PD-L2), contributing to recurrence. They show that PD-L2 blocking combined with chemotherapy is therapeutically beneficial because it reduces senescent cells and immunosuppressive cell recruitment.
Huang et al. show that ADAM9 loss upregulates PAI-1, promoting its interaction with KRAS and resulting in selective lysosomal degradation of KRAS. They also identify a small-molecule inhibitor of ADAM9 with therapeutic benefits in the context of PDAC.
Theodorescu and colleagues describe a Molecular Twin approach that integrates multi-omic and computational pathology data from patients with pancreatic ductal adenocarcinoma using artificial intelligence to predict clinical outcomes.
Manchado and colleagues combine CRISPR screening and transcriptomics to identify INPP5A as a dependency and therapeutic target in uveal melanoma driven by mutations in GNAQ/GNA11 and show that IP4 levels correlate with sensitivity to INPP5A loss.
Bagley et al. conduct a phase 1 trial to study safety and tolerability of CAR T-EGFRvIII cells administered concomitantly with PD-1 inhibition via pembrolizumab in patients with glioblastoma and show tolerability, but without signs of efficacy.
Jin and colleagues show that myeloid cells in patients with colorectal cancer exhibit increased expression of SIRPA and that Sirpa deficiency on macrophages reprograms the tumor microenvironment and enhances the function of antitumor CD8+ T cells.
Kumar et al. show that the lncRNA Malat1 prevents gasdermin D-mediated pyroptosis induction, in turn suppressing inflammatory cell death and mediating immune evasion and metastasis.
Sherman and colleagues show that ATX suppresses the accumulation of eosinophils in the tumor microenvironment of pancreatic cancer via suppression of CCL11 expression and find that ATX inhibition increases eosinophil influx, promoting tumor cell death.
Leibold and colleagues develop a method to somatically introduce oncogenic lesions into the stomach epithelium, which recapitulates the histological, molecular and clinical features of human gastric cancer.
Warner et al. analyze tumor tissue and ctDNA from patients with de novo metastatic castrate-sensitive prostate cancer and find high intratumoral heterogeneity, suggesting that genomic profiling of multiple samples per patient is needed for accurate outcome prediction.
Rich and colleagues identify that lymphatic endothelial-like cells in glioblastoma drive the growth of cancer stem cells via CCL21–CCR7 signaling, inducing KAT5 to acetylate HMGSC1, which enhances its protein stability and cholesterol synthesis.
Poeck and colleagues identify a microbiome signature in patients receiving allogenic stem cell transplantation, which is associated with protective immune-modulatory metabolites, improved survival and less transplant-related mortality.
Davies et al. show that skin PD-1+Vδ1+ cells show a transcriptional program of tissue residence and self-renewal, are functionally distinct from colocalized PD-1+CD8+ T cells and retain effector function that is derepressed by checkpoint blockade.
Ginhoux and colleagues perform multi-omic characterization of hepatocellular carcinoma and identify an onco-fetal niche that includes fibroblasts, macrophages and endothelial cells and influences immunotherapy response and relapse.
Simon and colleagues show that liver cancer cells undergo cell cycle arrest and senescence upon deprivation of methionine and identify GSK3 inhibitors as a senolytic to selectively deplete MAT2A inhibited senescent liver cancer cells.
Payton et al. develop small-molecule inhibitors of kinesin KIF18A able to selectively kill cancer cells with high chromosomal instability and demonstrate that the inhibitors are therapeutically beneficial in cancer patient-derived in vivo models.
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.
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.