News & Views

Combinations of immune-checkpoint blockade and radiotherapy to modulate antitumor immunity have mainly focused on manipulating T cells. A study now shows that combining radiotherapy with activation of macrophages yields potent, abscopal effects in mouse tumor models that may be ready for translation into early clinical trials.

Pancreatic ductal carcinoma exists within a heterogenous and complex microenvironment that imposes austere conditions with limited nutrient availability. Clonally separable neoplastic cell populations are now shown to segregate into two distinct metabolic configurations, facilitating symbiotic intratumoral crosstalk to support survival and growth.

Immunovirotherapy is a promising therapeutic strategy for glioblastoma (GBM), a deadly tumor for which effective treatments remain a clinical need. A new study describes an oncolytic herpes simplex virus (oHSV) armed with a bispecific anti-EGFR–CCL5 fusion protein that activates innate and adaptive antitumor immune responses that are highly efficacious in preclinical GBM models.

Intratumoral activation of the complement cascade may have therapeutic potential in patients with lung cancer with strong EGFR signaling, shows a new study. EGFR-triggered expression of CD55 and CD59 prevents opsonization of tumor cells, inhibits antitumor immunity and confers resistance to immune-checkpoint inhibitors.

The efficacy of talazoparib and other PARP inhibitors has been primarily reported in germline BRCA mutation carriers. New results establish germline mutations in PALB2, but not in other homologous recombination (HR) genes, as targets for PARP inhibitors in breast cancer, whereas the added predictive value of HR signatures remains uncertain.

Increasing evidence links RNA methyltransferases to DNA damage repair. METTL16 is now shown to antagonize homologous recombination by preventing DNA-end resection via MRE11. Thus, METTL16 may represent a cancer vulnerability that can be used to identify patients able to benefit from combination therapies with DNA-damaging agents.

Therapeutic resistance in prostate cancer can be driven by lineage plasticity, but the mechanisms behind this are unclear, and therapies to prevent or reverse the process are nonexistent. A new study reveals the JAK/STAT signaling axis as a driver of lineage plasticity with tremendous therapeutic potential.

The identification of tumor-reactive T cells using phenotypic markers is now well established in treatment-naive tumors. It is unclear, however, whether these markers can also be useful after immune checkpoint blockade (ICB). A new study finds that CXCL13 expression robustly identifies tumor-reactive T cells before and after ICB and is associated with treatment response.

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.

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.

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.

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.