Reviews & Analysis

Glioblastomas have limited treatment options and dire prognoses. A study now shows that GAP43-mediated transfer of functional mitochondria from astrocytes to glioblastoma cells leads to metabolism, signaling and epigenome remodeling that favor tumor growth, thus highlighting GAP43 inhibition as a promising therapeutic strategy for glioblastoma.

As we age, organs undergo architectural and functional changes that deeply affect the fate of disseminated tumor cells (DTCs). A study now adds further complexity to this picture by revealing a role for the age-induced, fibrosis-associated factor PDGF-C in enabling ER⁺ DTCs to reawaken in aging lungs and thrive as overt metastasis.

The lack of tumor-specific surface antigens has limited the application of CAR T cells in solid tumors. A new AND-gated CAR T cell system repurposes proximal T cell signaling proteins to restrict activation to dual antigen encounter, mitigating on-target, off-tumor toxicity while preserving antitumor efficacy in preclinical models.

The response rates of pediatric cancers to immune checkpoint inhibitor therapies are disappointingly low, particularly when compared to the remarkable impact of these drugs in many adult cancers. A new study leverages clinical trial data to identify biomarkers that might improve patient selection in future clinical trials.

Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy. We examined the dynamic changes of immune cells that occur in the tumor microenvironment of radio-immunotherapy-treated glioblastomas and identified a subpopulation of regulatory T cells with increased immunosuppressive activity. Depletion of this cell population improved survival in a mouse model of glioblastoma.

Multiple myeloma is a rare and incurable cancer of plasma cells. To characterize this cancer, we developed an ex vivo drug screening method that combines imaging, deep learning and multiomics and applied it in an observational trial, uncovering new potential therapeutic strategies and underlying disease mechanisms.

Kimmelman and colleagues discuss the role of autophagy in tumor cells and of cell-nonautonomous autophagy in the microenvironment and host cells in supporting tumor growth and reflect on open questions in the field.

Lobular breast cancer is the second most prevalent breast cancer subtype, but clinical trials have not focused on these patients. The GELATO study reveals the feasibility of trials that are specific for this difficult to treat cancer and indicates that patients with lobular breast cancer can benefit from immunotherapy using PD-L1 blockade.

Clinical utility of T cell engagers (TCEs) in cancer immunotherapy for solid tumors is hampered by on-target off-tumor activity and dose-limiting adverse events. A study now proposes a solution to tackle these challenges through the design and preclinical characterization of extended half-life TCEs that are conditionally activated in the tumor microenvironment.

Although targeting cancer cells on the basis of tissue-specific expression of key factors is an important strategy in precision oncology, few such therapies exist. Chemical screening now identifies YC-1 as a tissue-specific anti-cancer compound that is activated in the liver by the sulfotransferase enzyme SULT1A1.

Saur and colleagues provide an overview of single-cell analyses in pancreatic cancer and discuss their implications for our understanding of heterogeneity and plasticity in the tumor and its microenvironment.

A study of the immune microenvironment of estrogen receptor-positive (ER⁺) invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) identifies pro-tumor and anti-tumor macrophages as key players that can potentially influence disease outcome.

Transactivation hubs and related biomolecular condensates are emerging as relevant molecular players in cancer biology. A new study now links PD-L1 upregulation on the cancer cell surface and IRF1–KAT8 transactivation hubs at PD-L1 loci. Therapeutic targeting of these hubs holds potential to unleash antitumor immunity.

Speiser and colleagues review the latest advances in understanding of the biological roles of CD4⁺ T cells in cancer immunology and applications for immunotherapy.

In this review article, Christ and colleagues discuss the recent developments in antibody-based cancer therapies.

Shaw and colleagues discuss the oncogenic roles of ALK in lung cancer, targeting approaches and the mechanisms underlying acquired resistance to ALK-directed therapy.

High-fat diet and the secretome of breast tumors prime distant organs for metastasis formation. During lung priming, alveolar type II cells increase the release of palmitate, which is oxidized to acetyl-CoA by metastasizing breast cancer cells, where the increased acetylation of the NF-κB subunit p65 activates a pro-metastatic transcriptional program.

Using an unbiased algorithm based on kinase–phosphorylation site interactions that is applicable to any proteomic dataset, we identified and experimentally validated two protein kinases (PKCδ and DNA-PKcs) as the master kinases that drive two functional subtypes of glioblastoma multiforme and are potential therapeutic targets of other cancer subtypes.

Somatic mutations in cancer genomes are caused by multiple mutational processes, each generating characteristic mutational signatures. Our systematic mutational signature analysis of single base substitutions and small insertions and deletions in pediatric cancers indicates that the contribution of signatures of homologous recombination repair defect is limited and identifies a leukemia-specific signature.

Patients with blood cancer have fewer antibodies after SARS-CoV-2 vaccination — but recent work shows that these antibodies seem to bind to viral spike protein more strongly than those in matched controls. In addition, another study finds that convalescent or vaccinee plasma might improve COVID-19 outcomes in those with blood cancer.