Reviews & Analysis

Immune checkpoint inhibitors (ICIs) are effective for many cancers but can be limited by inflammatory toxicities. Little is known about how ICIs affect the reproductive system. New research in animal models with and without tumours demonstrates that ovarian reserves are depleted in mice treated with ICIs, which may influence fertility.

Structural variants (SVs), such as copy-number alterations, rearrangements and aneuploidies, are common somatic changes in cancer genomes and rich sources of driver oncogenes, but reconstructing these from sequencing data is a challenge. Two new studies shed light on the diversity and importance of the SV landscape in cancer.

Brody and colleagues discuss the current status and potential of cancer vaccines, highlighting challenges and opportunities to advance promising candidates to the clinic.

How pancreatic ductal adenocarcinoma persists despite limited nutrients within the tumor microenvironment warrants further investigation. A study now identifies a metabolic mechanism wherein NUFIP1 induces release of nucleosides from cancer-associated fibroblasts, leading to activation of MYC-dependent glucose consumption and tumor growth.

Though HER2 (ERBB2) exon 20 insertion mutations occur in ~2% of non-small-cell lung cancers, molecular targeted therapies for such cancers have been lacking. A study now identifies selective HER2 inhibitors that have marked efficacy against tumors driven by HER2 exon 20 insertions, without inhibiting wild-type EGFR activity.

Despite the remarkable success of chimeric antigen receptor (CAR) T cell therapies in the treatment of hematological malignancies, this strategy remains challenging in solid tumors. One major obstacle is the hostile immunosuppressive tumor microenvironment. New research demonstrates that targeting PARP11 can overcome this immunosuppression and boost CAR T cell efficacy through stabilization of IFNAR1.

Inhibition of XPO1-mediated nuclear export by selinexor represents a promising therapeutic strategy in acute myeloid leukemia. Because XPO1 is not specific for tumor-suppressive proteins, selinexor may also activate pro-oncogenic processes. A study now shows that inhibition of selinexor-induced, purinergic receptor–mediated AKT activation potentiates its anti-leukemic activity.

Lavie et al. review the recent advances in the field of cancer-associated fibroblasts, including their tissue-specific complexity and overall plasticity, as revealed by single-cell technologies.

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 phenotypes of γδ T cells infiltrating human tumors and their role in anti-tumor immunity remain poorly understood. A new study demonstrates that Vδ1 lymphocytes with cytolytic potential and features of tissue-resident-memory differentiation are predictive of survival in patients with non–small-cell lung cancer.

Prognostic information for patients with ovarian cancer is captured in clinico-genomic data, histopathology slides and computed tomography imaging; however, how to integrate these data is unclear. A study now presents a method for combining complementary data types to stratify risk and aid treatment selection in patients with ovarian cancer.

Tumor mutational burden (TMB) has received significant attention within ongoing pursuits of biomarkers of response to immune checkpoint inhibitors, and notably received FDA approval as a companion diagnostic biomarker for pembrolizumab. Here, four experts discuss the utility, challenges, and open questions surrounding TMB in the context of cancer immunotherapy.

Melero and colleagues discuss the current landscape of immunotherapy combinations, ongoing clinical studies and the translational implications for efficacy and safety across tumor types.

Therapy resistance limits the clinical success of tyrosine kinase inhibitors (TKIs) in ALK-positive non-small cell lung cancer. A study now proposes a framework to identify compound resistance mutations to the lorlatinib TKI and provides structure-based drug design approaches to overcome resistance mediated by ALK(G1202R) or ALK(I1171N/S/T).

The lethality of prostate cancer is driven by its progression to a castration-resistant state. A new study identifies gremlin 1 (GREM1) as an agonist of fibroblast growth factor receptor 1 (FGFR1) that drives such progression when androgen receptor (AR) signaling is low, nominating GREM1 as a therapeutic target for prostate cancer with low AR activity.

Acute myeloid leukemia (AML) is characterized by distinct genetic and molecular alterations, including rearrangements in the mixed lineage leukemia (MLL) gene. A study now presents a therapeutic strategy for MLL-rearranged (MLL-r) AML that exploits a unique co-dependency on IKAROS and MENIN.

Patients with cancer are known to be at increased risk of infection and severe complications from COVID-19, with vaccination being key for their protection. A prospective study now evaluates the effect of vaccination against COVID-19 on the immune response mounted by patients with lymphoma.

Stanley and Abdel-Wahab review the latest insights into the biological mechanisms of RNA splicing dysregulation in cancer and the emerging landscape of therapeutic opportunities in this field.

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.