Reviews & Analysis

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.

Inhibiting glutamine metabolism has thus far been clinically challenging. Two studies in preclinical mouse models now report that, in contrast to the failure of glutaminase inhibitors, broad suppression of glutamine metabolism with glutamine analogs delivered to tumors results in reduced pancreatic cancer growth, with targetable resistance mechanisms.

Van Loo and colleagues review the mechanistic underpinnings of large genomic alterations and their roles in tumor development and evolution.

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.

Schulze and colleagues discuss the latest advances in understanding the role of lipids in cancer progression and metastasis and reflect on opportunities to target lipid metabolism in tumors.

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.

Cancer cells seed distant tissues and remain dormant before re-entering the cell cycle to form metastases. How tumor dormancy is maintained and how cells exit dormancy is poorly understood. A study shows that the lncRNA MALAT1 reactivates dormant cancer cells by upregulating serpin protease inhibitors in tumor cells to evade CD8⁺ T cells.

In vitro-transcribed RNA is a promising emerging class of therapeutic, but the poor specificity of cargo RNAs so far has limited their application in cancer immunotherapy. A new study reports the delivery of a synthetic circular RNA with inline cis-acting translational elements — encoding an engineered, mitochondrion-specific oncolytic protein — that shows both therapeutic and prophylactic potential against adenocarcinoma.

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.