Reviews & Analysis

A CRISPR dropout screen for tRNA regulators identified YRDC as the top essential gene in glioblastoma stem cells. Threonine acts as a substrate of YRDC to facilitate the N⁶-threonylcarbamoyladenosine (t⁶A) tRNA modification and shift translation toward mitosis-related genes with a codon bias. Our findings support targeting glioblastoma growth by a well-tolerated dietary therapy.

Pancreatic cancer liver metastases show high levels of immunosuppressive macrophages, which promote tumor growth. We found that blocking the efferocytosis pathway during early-stage metastasis in a mouse model inhibited the development of immunosuppressive activity in monocyte-derived macrophages, which restored T cell activation and reduced the metastatic tumor burden.

Our study reveals that the LGR4–Wnt signaling pathway dictates both ferroptosis and stemness traits to confer drug resistance to tumor cells. We thus generated a monoclonal antibody against LGR4 that blocks LGR4–Wnt signaling and sensitizes chemotherapy-resistant colorectal cancer tumors via selective promotion of ferroptosis.

Using CRISPR–Cas9 screens, we found that cancer-cell-intrinsic loss of Pip4k2c conferred liver-metastatic organotropism in melanoma through hypersensitization to insulin-mediated PI3K–AKT signaling via co-optation of distinct hepatic metabolic cues. Additionally, we showed that combinatorial therapies that abolished physiological and drug-induced changes in glucose and insulin levels specifically reduced liver metastasis.

Mitochondrial DNA mutations are present in over 50% of all cancers, and truncating mutations in several genes encoding components of complex I of the respiratory chain are most recurrent. We found that these mutations are a source of Warburg-like metabolic shifts that promote a pro-inflammatory immunological state, enhancing sensitivity to checkpoint blockade.

Senescent cancer cells, which are characteristically present in tumors after genotoxic therapies, upregulate the immune checkpoint ligand programmed cell death 1 ligand 2 (PD-L2). We show that genetic or pharmacological ablation of PD-L2 prevents the accumulation of intratumoral senescent cells, reducing the recruitment of immunosuppressive myeloid cells and facilitating tumor clearance by T cells.

Imetelstat is a first-in-class telomerase inhibitor with efficacy in a number of blood cancers. Intriguingly, telomere lengths do not predict patient responses to imetelstat. We now show that imetelstat causes cell death by a mechanism that involves two regulators of fatty acid metabolism (FADS2 and ACSL4), driving excessive lipid reactive oxygen species formation and ferroptosis.

We applied an artificial intelligence (AI) approach to a dataset of clinical and advanced multi-omic molecular features from patients with pancreatic adenocarcinoma to predict survival. The results reveal a tumor-type-agnostic platform that can identify parsimonious and robust clinical prediction biomarkers, catalyzing the vision to democratize precision oncology worldwide.

Chromosomal instability (CIN) (a hallmark of human cancer) is caused by persistent errors in chromosome segregation during mitosis. Pharmacological inhibition of the mitotic kinesin KIF18A selectively exploits a mitotic vulnerability for which cancer models with CIN are enriched, which leads to robust anti-cancer effects and durable tumor regression in mice.

Microbiome diversity has been associated with improved outcomes after allogeneic stem-cell transplantation in patients with hematological cancers. Multimodal analysis of intestinal microbiome and metabolome data helped identify immunomodulatory microbial metabolites that were predictive of survival, transplant-related mortality and cancer relapse. These metabolites were products of short-chain-fatty-acid-synthesis pathways, and their associated genes were expressed by both bacterial species and bacteriophages.

Genomic features of de novo metastatic prostate cancer can clarify prognosis and direct therapy. Using multi-region profiling of synchronous primary and metastatic patient tissues, we reveal the complex evolutionary histories of this lethal disease and identify strategies to better capture the genomic features of dominant metastatic populations.

We developed a method for generating dendritic cell progenitors (DCPs) from hematopoietic stem and progenitor cells isolated from bone marrow or blood. When engineered to express IL-12 and FLT3L, these DCPs reprogram the tumor microenvironment and elicit anti-tumor immunity without the need for ex vivo antigen loading.

We sought to develop a pharmacologically advanced inhibitor of the oncoprotein RET. Vepafestinib potently inhibited on-target mutants that confer resistance to approved RET inhibitors while exerting superior efficacy against intracranial disease due to enhanced penetration and retention in the brain.

Resected pancreatic cancer treated pre-operatively with chemotherapy is enriched for cells that co-express GATA6, KRT17 and CYP3A. Persistent expression of GATA6^hi and KRT17^hi is associated with poor survival after treatment with mFOLFIRINOX, but not gemcitabine. CYP3A-expressing drug detoxification pathways metabolize the prodrug irinotecan, a constituent of mFOLFIRINOX, leading to persistent drug tolerance.

Immunosuppressive myeloid cells, which are associated with resistance to anti-PD1 therapy in patients with glioblastoma, have high expression of KDM6B, an epigenetic enzyme. Deletion or inhibition of KDM6B reprograms the myeloid cells to an immunostimulatory phenotype and thereby overcomes resistance to anti-PD1 therapy in preclinical models of glioblastoma.

Treatment with immune checkpoint inhibitors (ICIs) has improved the survival of patients with metastatic melanoma. However, although ICIs are promising for achieving lasting clinical responses, only a subset of patients receive substantial benefit. Our results suggest that the IL-17 pathway supports the response of melanoma to dual ICI therapy and might represent a biomarker for patient stratification.

This study reveals the previously underappreciated roles of CD25 (IL-2 receptor subunit-α) in IL-2 biology and cancer immunotherapy and provides mechanistic insights into the rational design of more-effective IL-2-based therapeutic agents for cancer treatment.

Tyrosine kinase inhibitors that target anaplastic lymphoma kinase (ALK) have greatly improved the survival of patients with ALK-rearranged non-small-cell lung cancer, but they are insufficient to achieve a complete cure. A newly developed vaccine elicited a strong immune response specifically against ALK that eradicated primary tumors and prevented the onset of metastatic disease in mice.

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.