Reviews & Analysis

A genome-wide CRISPR screen finds CIP2A as a new synthetic lethal target for BRCA1- and BRCA2-deficient cells. Unlike PARP inhibition that increases replication-induced DNA double-strand breaks and radial chromosomes, depleting CIP2A or disrupting its interaction with TOPBP1 increases micronuclei and chromosomal missegregation, revealing a mitotic target for BRCA-mutated tumors.

Mutations arising from APOBEC3-induced cytidine deamination are often found in advanced human cancers, yet how APOBEC3 promotes tumor progression remains poorly understood. A new study finds that APOBEC3A drives chromosomal instability in a deaminase-domain-independent manner, thereby promoting STING-dependent cancer metastasis.

Despite the profound clinical success of immune-checkpoint inhibitors, their effectiveness is limited by intrinsic and acquired resistance. Bullman, Zitvogel and colleagues provide their views on two clinical trials modulating the microbiome of immunotherapy-resistant patients with melanoma via transplantation of fecal microbiota from patients who responded to immunotherapy.

Twelve early-career investigators share their thoughts on the challenges faced by their teams and communities during the past year, and look ahead to new opportunities for 2022.

Cancer is associated with higher risk of severe COVID-19 outcomes. Two studies prospectively analyze the immunological and clinical characteristics of a large cohort of patients with cancer following SARS-CoV-2 infection or vaccination, providing important clinical insights to improve the management of such vulnerable patients.

Glioblastoma multiforme (GBM) is a lethal form of primary brain cancer. A new study now implicates beta-secretase 1 (BACE1) as a crucial regulator of pro-tumoral IL-6–STAT3 signaling in GBM-associated macrophages. An effective BACE1 inhibitor, clinically developed for Alzheimer’s disease, may offer new hope for GBM treatment.

The mechanisms regulating the progression of benign tumors to malignant carcinomas remain incompletely understood. A new study identifies the transcription factor NR2F2 as a specific regulator of this transition that plays critical roles in the maintenance of the malignant tumor state.

Acute myeloid leukemia (AML) is a heterogeneous disease with limited therapeutic options. A new study identifies leukocyte immunoglobulin-like receptor 3 (LILRB3) as a marker of monocytic AML, with the ability to modulate NF-κB signaling and to promote survival and immune evasion. Blockade of LILRB3 signaling could provide a novel therapeutic strategy in monocytic AML.

Shedding light on epigenetic mechanisms controlling anti-tumor immune responses, a new study shows that the tumor-intrinsic ring finger protein 2 (RNF2), the catalytic subunit of Polycomb repressor complex 1 (PRC1), acts as a negative regulator of a collaborative NK and CD4⁺ T cell anti-tumor immune response against breast cancer.

Clinical interpretation of cancer genomes for therapy selection and clinical hypothesis generation is an urgent and complex endeavor. A new study brings together a diverse set of data sources to automatically prioritize first- and second-order genomic alterations to provide a meaningful set of interpretations based on a patient’s molecular profile.

DNA methyltransferase inhibitors are widely used in preclinical and clinical studies, but poor pharmacokinetics and low efficacy in solid tumors limit their therapeutic use. A new study reports the development and characterization of a specific, non-covalent DNA methyltransferase inhibitor with more-durable DNA hypomethylation and lower toxicity than that of nucleoside analogs.

CAR T cell therapies have made great strides in the clinic; however, multiple hurdles limit the efficacy of this approach for solid tumors. A new study has developed an optimized, dual-targeting CAR T cell that overcomes several of these challenges by enhancing T cell persistence and reducing therapy escape due to antigen loss.

Pseudouridine is the most abundant RNA modification, but its biological role remains poorly understood. A study now finds dysregulated pseudouridine synthase PUS7 in glioblastoma and demonstrates that pharmacological inhibition of PUS7 leads to reduced tumorigenesis, which underpins the therapeutic potential of targeting epitranscriptomic regulators in cancer.

Combining radiation and immune checkpoint blockade is a promising treatment strategy, yet the mechanisms and optimal dosing strategies are not well known. A new study finds that a specific radiation dose can activate secretory club cells to promote the anti-tumor effects of radiotherapy combined with immunotherapy in NSCLC.

Ding and colleagues discuss the era of pan-cancer analysis, covering the fundamental insights gained, unique opportunities and challenges, and the future of such approaches in the basic and clinical space.

Drug resistance may pre-exist or arise during therapy, but how precisely cancer treatment itself influences these processes is a major gap in the understanding of therapy resistance in cancer. A study of acute lymphocytic leukemia now provides direct evidence of thiopurine-induced mutations in the gene encoding the tumor suppressor p53 that result in multi-drug-resistant relapse.

Melenhorst and colleagues review the current status of chimeric antigen receptor T cell therapies, focusing on the rapid progress achieved in this area of immunotherapy, but also the challenges to be overcome.

Immuno-oncology approaches have shown little efficacy against high-grade glioma, a devastating manifestation of brain cancer. A new study now finds a metabolic vulnerability in IDH1-mutant glioma that can be targeted to reprogram tumor-infiltrating macrophages and create a tumor microenvironment that is more responsive to immune-checkpoint therapy.

Institutional clinical data repositories provide a depth and consistency of data elements that is difficult to match even with data pooled from diverse sources. A study now demonstrates how real-world data and clinical encounters can be captured in an integrated ‘data story’ to enable continuous learning and hypothesis generation in oncology.

Prostate cancer is largely unresponsive to immunotherapy. A new study finds elevated expression of the chemokine IL-8, or its mouse homolog Cxcl15, in prostate cancer after castration, which leads to the recruitment of immunosuppressive myeloid cells. Blocking tumor infiltration with these cells could improve the response to immune-checkpoint inhibition and androgen-deprivation therapy.