Research Briefing

Chimeric antigen receptor (CAR) T cells are effective for the treatment of therapy-resistant blood cancers but not solid tumors. We used a well-studied mutant c-KIT protein (c-KIT D816V) as a co-stimulatory domain to generate CAR T cells with strong IFNγ signaling that were able to overcome the immunosuppressive microenvironment of solid tumors.

An antisense RNA, NQO1-AS, binds and stabilizes its sense strand, upregulating the redox enzyme NQO1 in metastatic breast cancer cells. Overexpression of NQO1 facilitates lung colonization by suppressing oxidative stress and ferroptosis, and cancer cells dependent on this pathway can be targeted by a combined therapy that induces ferroptosis while simultaneously inhibiting NQO1.

Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy. We examined the dynamic changes of immune cells that occur in the tumor microenvironment of radio-immunotherapy-treated glioblastomas and identified a subpopulation of regulatory T cells with increased immunosuppressive activity. Depletion of this cell population improved survival in a mouse model of glioblastoma.

Multiple myeloma is a rare and incurable cancer of plasma cells. To characterize this cancer, we developed an ex vivo drug screening method that combines imaging, deep learning and multiomics and applied it in an observational trial, uncovering new potential therapeutic strategies and underlying disease mechanisms.

Lobular breast cancer is the second most prevalent breast cancer subtype, but clinical trials have not focused on these patients. The GELATO study reveals the feasibility of trials that are specific for this difficult to treat cancer and indicates that patients with lobular breast cancer can benefit from immunotherapy using PD-L1 blockade.

A study of the immune microenvironment of estrogen receptor-positive (ER⁺) invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) identifies pro-tumor and anti-tumor macrophages as key players that can potentially influence disease outcome.

High-fat diet and the secretome of breast tumors prime distant organs for metastasis formation. During lung priming, alveolar type II cells increase the release of palmitate, which is oxidized to acetyl-CoA by metastasizing breast cancer cells, where the increased acetylation of the NF-κB subunit p65 activates a pro-metastatic transcriptional program.

Using an unbiased algorithm based on kinase–phosphorylation site interactions that is applicable to any proteomic dataset, we identified and experimentally validated two protein kinases (PKCδ and DNA-PKcs) as the master kinases that drive two functional subtypes of glioblastoma multiforme and are potential therapeutic targets of other cancer subtypes.

Somatic mutations in cancer genomes are caused by multiple mutational processes, each generating characteristic mutational signatures. Our systematic mutational signature analysis of single base substitutions and small insertions and deletions in pediatric cancers indicates that the contribution of signatures of homologous recombination repair defect is limited and identifies a leukemia-specific signature.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of mortality worldwide. Integrative analysis of the genome, transcriptome and proteome of PDAC tissues, also known as proteogenomic analysis, provides insight into the biology of this cancer and is a resource for therapeutic discovery.

Modulation of T cell immune checkpoints combined with inhibition of chemokine receptors on myeloid-derived suppressor cells can reprogram the highly suppressive tumor immune microenvironment of pancreatic ductal adenocarcinoma (PDAC), and generates durable complete responses in a PDAC mouse model. These results provide a testable clinical regimen for human PDAC.

Mesenchymal-like and pluripotency-like programs coordinate the dissemination and long-lived dormancy of early breast cancer cells. The transcription factor ZFP281 controls these programs, preventing the acquisition of an epithelial-like proliferative phenotype and serving as a previously unrecognized barrier to metastasis.

Immunotherapy has shown great promise in the treatment of patients with advanced non-small-cell lung cancer. We show that integration of data collected during diagnostic clinical work-up with machine learning has the potential to improve predictions of response to immunotherapy and to identify the patients most likely to benefit.

Many patients with colorectal cancer (CRC) relapse after chemotherapy. Tumor cells that do not completely adapt to their environment (owing to an incomplete set of CRC driver mutations) enter a latent state, in which the expression of Mex3a is upregulated. Mex3a⁺ cells are chemoresistant and reactivate after treatment, which leads to regeneration of the disease.

The transcription factor IKAROS is essential to maintaining a leukemogenic gene-expression profile mediated by transcription factors encoded by HOXA@ and MEIS1 in MLL1-rearranged (MLL-r) acute myeloid leukemia. Pharmacological degradation of IKAROS increases the effectiveness of inhibitors of the MLL1–MENIN protein–protein interaction, which leads to more-robust disruption of leukemogenic transcriptional networks and enhanced therapeutic benefit in preclinical models.

People with lymphoma have immune defects that compromise the immune response to vaccination. A prospective observational study of 457 people with lymphoma showed improvement in antibody and T cell responses after the third vaccine dose except in those who received anti-CD20 antibody therapy within a year prior to vaccination.

Mitochondrial fission in macrophages is essential for the phagocytosis of tumor cells. Resistance of tumor cells to phagocytosis involves overexpression of GFPT2, an enzyme involved in glutamine metabolism; this results in lower nutrient availability for macrophages to support mitochondrial fission and prevents assembly of the phagocytic machinery.