News & Views

Cancer vaccines can elicit tumor-specific T cells, but sustaining their function via immune checkpoint therapy (ICT) may be required for robust anti-tumor immunity. A new study reveals that neoantigen cancer vaccines synergize with anti-PD-L1 ICT in a preclinical model and provides mechanistic insights into this synergy.

Patients with KRAS-mutant colorectal cancers do not respond to cetuximab, a monoclonal antibody against EGFR. A new proof-of-concept study presents a bispecific antibody with the ability to trigger EGFR degradation in LGR5⁺ cancer stem cells, and robust anti-tumor activity in KRAS-mutant and wild-type colorectal cancers.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have revolutionized the treatment of EGFR-mutant non-small cell lung cancer; however, secondary resistance limits their efficacy, emphasizing the need for newer approaches. A study now shows preclinical development of allosteric EGFR inhibitors that overcome acquired therapy resistance.

Severe side effects limit the therapeutic potential of checkpoint control and immunomodulatory antibodies in immunotherapy of cancer. A new study demonstrates that bispecific antibodies directing the immunostimulatory activity of CD40-specific antibodies on dendritic cell subsets may allow a greater therapeutic window of opportunity.

Cellular communication in the tumor microenvironment is crucial for T cell activation; however, the molecular features of the T cell–antigen-presenting cell interaction are still poorly understood. A new study utilizes RNA sequencing of physically interacting cells to reveal that PD-1⁺CXCL13⁺ helper T cells in tumors, primed by dendritic cells, are important for the response to immunotherapy.

Two of the first patients with cancer treated with chimeric antigen receptor-modified (CAR) T cells have been cancer free for a decade. A new study uses single-cell sequencing technologies to provide a window into the evolution of their CAR T cells over the course of the ten-year remission period.

The mitochondrial arm of the one-carbon pathway, which is essential for nucleotide synthesis, becomes dominant in cancer cells due to overexpression of several enzymes of the pathway, including MTHFD2. A study now reports on a high-affinity inhibitor of MTHFD2 that starves cancer cells of DNA building blocks and shows potential for selective tumor targeting.

Neutrophils may obtain either pro- or anti-tumorigenic phenotypes depending on environmental cues. A new study reports that cancer radiotherapy induces a neutrophilic response associated with tissue repair and leads to enhanced metastatic spread, highlighting a mechanism by which neutrophils promote metastatic tumor growth.

New research shows that comprehensively characterized patient-derived xenografts (PDXs) of breast cancer can be adapted to high-throughput drug screening and can be used as personalized patient avatars to inform clinical decision-making. This work substantially enhances the repertoire and sophistication of PDXs for research into breast cancer.

Although many potential targets have been identified, effective, specific therapies for metastatic cancers are still lacking. Two studies now identify small-molecule inhibitors of MTDH–SND1 interaction that potently suppress breast cancer progression and metastasis via concerted cancer-cell-autonomous effects and immune modulation.

The architecture of tumor collagen greatly influences tumor biology and therapeutic response. Two new studies identify tumor DDR1 as a central player in stromal collagen deposition and organization in the primary tumor and in disseminated tumor cells, resulting in immune exclusion or sustained dormancy, respectively.

A potential translational strategy to treat brain metastases is the induction or maintenance of proliferative dormancy in tumor cells. A new study shows that dormancy in breast cancer brain metastasis is maintained in the perivascular niche by astrocyte endfoot secretion of laminin-211, causing tumor cell membrane sequestration of YAP.

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.

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.