2023 in Review

We bid farewell to the past year with a set of specially commissioned commentaries, news articles and a selection of highlights from the cancer research literature.

Bispecific T cell engagers and antibody–drug conjugates took center stage in a year that also brought several new kinds of small-molecule therapies.

From halted healthcare services and corrupted code to stolen personal data held for ransom, cyberwarfare knows no boundaries. Healthcare providers are now facing unprecedented challenges from hackers, with uncertain consequences to patients with cancer.

Twelve early-career investigators share their thoughts on the experiences they had starting their laboratories in 2023 and reflect on the opportunities they seized and the challenges they faced.

Real-world data (RWD) and real-world evidence (RWE) from heterogeneous data sources has the potential to transform oncology research, especially when coupled with artificial intelligence (AI). We discuss the issues involved in primary data capture and post-hoc AI analysis and propose using AI to support the capture of primary RWD.

Neoantigen immunogenicity prediction is a burgeoning field with vast potential; however, the shortage of high-quality data and biases in current datasets limit model generalizability. Here we discuss some of the pitfalls that may underly this limited performance and propose a path forward.

Owing to high response rates, the Food and Drug Administration has approved both gene- and immune-targeted drugs for tumor-agnostic, genomic biomarker-based indications, for lethal solid and blood cancers. We posit that current data support tissue-agnostic activity as a paradigm, rather than an exception to the rule.

Voorwerk et al. report the clinical and translational results from a phase II trial evaluating the combination of carboplatin with anti-PD-L1 in patients with invasive lobular breast cancer, who have been underrepresented in clinical trials so far.

Watson et al. demonstrate that astrocyte mitochondria can be horizontally transferred to glioblastoma cells in a GAP43-dependent manner, leading to changes in mitochondrial respiration and metabolism that promote proliferation and tumor growth.

Hagenbeek et al. identify a small-molecule pan-TEAD inhibitor that blocks the interaction between YAP/TAZ and TEAD proteins. They demonstrate that treatment with the inhibitor leads to antitumor activity and can synergize with KRAS G12C inhibition.

Iavarone and colleagues develop a computational approach called SPINKS to identify master kinases for functional subtypes of human glioblastoma defined using integrated multi-omics data, which show potential as subtype-specific therapeutic targets.

Shlien and colleagues report on 300 patients from the SickKids Cancer Sequencing program and identify clinically actionable variants in 56% of the patients by profiling somatic and germline data at multiple clinical time points.

Fecci and colleagues show that tumor cells having lost MHC-I, a major mechanism of immune escape, are amenable to killing by CD8⁺ T cells through an MHC-I-independent, alternative pathway via NKG2D and NKG2DL interaction and granzyme.

Fendt and colleagues find that pre-metastatic niche formation and a high-fat diet increase palmitate availability in future organs of metastases and show that breast cancer cells use palmitate to generate acetyl-CoA, acetylate the NF-κB subunit p65 and induce pro-metastatic signaling.

Feng et al. describe a gasdermin D circRNA-based approach to target mitochondrial inner membrane cardiolipin and demonstrate that this tool can trigger mitochondrial autophagy and affect tumor growth and immunity in EIF4G2⁺ /PTBP1⁺ pan-adenocarcinoma.

Bassani-Sternberg and colleagues perform multiregion immunopeptidomics, genomics and spatial transcriptomics in patient lung cancer samples, demonstrating heterogeneity in the immunopeptidome associated with degrees of immune cell infiltration.

Sorger and colleagues present Orion, a technique to analyze H&E histology and multiplex immunofluorescence imaging data from the same cells, which they apply to human colorectal cancer samples to identify spatial biomarkers of disease progression.

Schellenberger and colleagues engineer masked, conditionally active T-cell engagers targeting tumor antigens and CD3 and show potent, protease-dependent antitumor activity in mouse models, as well as safety in non-human primates.

Bousso and colleagues show that IFN-γ production is the dominant tumor elimination mechanism exerted by CD4⁺ CAR T cells and define tumor cell sensitivity to IFN-γ as a determinant of CD4⁺ CAR T efficacy.