Research Briefing

We developed and clinically implemented the genomic prostate cancer risk prediction model P-CARE that identifies men at a high or low risk of prostate cancer. P-CARE enabled the design and initiation of a precision screening trial across the national healthcare system in which it was developed.

Chimeric antigen receptor (CAR) T cell therapy for solid tumors faces substantial biological and clinical barriers. In a phase 1 clinical trial, we show that a hypoxia-responsive, carcinoembryonic antigen-targeted CAR T cell therapy is safe and elicits meaningful antitumor responses in patients with refractory solid tumors. Efficacy was enhanced when CAR T cells were delivered intraperitoneally, suggesting this approach overcomes regional immunosuppressive barriers.

GENEVA is a technique that enables high-resolution, single-cell analysis of pharmacogenomics by profiling pooled, genetically diverse tumors. In a proof-of-concept application, GENEVA uncovered mitochondrial hyperactivation as an on-target mechanism of cell death and identified epithelial-to-mesenchymal transition as a resistance pathway, revealing both mechanistic insights and targets for combination therapy.

Systemic delivery of oncolytic viruses has long been limited by rapid immune clearance, short circulation times and restricted spread within tumors. To overcome these challenges, we engineered an immune-cloaked, ultrasound-inducible oncolytic virus platform. By evading immune clearance and triggering pyroptosis to amplify viral replication within tumors, this approach enhances immune activation and drives potent tumor regression in preclinical models.

A phase 2 trial demonstrates that cryoablation followed by sintilimab (an anti-PD1 antibody) and lenvatinib yields a 75% objective response rate in chemotherapy-refractory advanced or metastatic intrahepatic cholangiocarcinoma. Multi-omics analyses reveal that enhanced immunogenicity and lymphocyte infiltration underpin the abscopal effect.

Oncogenic KRAS hijacks chromatin remodeling during pancreatitis-induced tissue regeneration to drive tumorigenesis. We found that the chromatin remodeler SMARCA5 cooperates with oncogenic KRAS to maintain the malignant chromatin state; its deletion blocked tumorigenesis while preserving pancreatic tissue repair.

Relapse after CAR T cell therapy is often caused by tumors that have low levels of the target antigen. By engineering a membrane-tethered version of the signaling adaptor SLP-76, we improved the ability of CAR T cells to respond to antigen-low tumors. This restored CAR T cell function in multiple preclinical models and offers a potential strategy to overcome this common form of resistance.

Bidirectional signaling between the brain and peripheral tumors plays a major part in cancer biology but is poorly understood. Stress-sensitive neurons in the lateral septum connect with the enteric nervous system via a polysynaptic circuit. Subsequently, these activated enteric cholinergic neurons promote tumor growth in colorectal cancer models.

We developed paclitaxome-2, an optimized version of the sphingomyelin-derived paclitaxel nanovesicle paclitaxome. Leveraging the cationization-enabled transcytosis machinery boosted tumor penetration, and incorporating CD47 ‘self’ peptide masking minimized phagocytosis. Co-delivery of gemcitabine or carboplatin improved therapeutic outcomes in advanced pancreatic cancer and post-surgical triple-negative breast cancer in mouse models.

We integrated multi-omics data to construct a dynamic epigenomic atlas of colorectal cancer, identifying functional cis-regulatory elements through CRISPR interference screening. Furthermore, we developed a functionally informed polygenic risk score based on cis-regulatory element variants for risk prediction and revealed an epigenetic mechanism that drives colorectal cancer progression.

In metastatic, immunologically ‘cold’ non-small cell lung cancer, the combination of radiation therapy and immune checkpoint inhibition (ICI) demonstrates heightened anti-tumor immune responses at non-irradiated sites and improved clinical responses compared with ICI alone. Radio-immunotherapy holds promise for patients with ICI-refractory lung cancer.

We investigated the early-stages of prostate cancer initiation. Deletion of Pten from epithelial basal cells in mice leads to cell plasticity, lineage infidelity and tumor formation, which are orchestrated by the activation of innate immunity and NF-κB signaling in prostate basal stem cells. Our findings have implications for human prostate cancer.

Extracellular DNA within neutrophil extracellular traps contributes to doxorubicin cardiotoxicity by interacting with CCDC25, a transmembrane DNA sensor on cardiomyocytes. This interaction promotes the generation of reactive oxygen species and activates autophagy, subsequently impairing cardiac function. Targeting CCDC25 mitigates cardiac damage and enhances the anti-tumor efficacy of doxorubicin, revealing a dual therapeutic strategy.

tRNA modifications are key regulators of translational reprogramming, although their role in colorectal cancer (CRC) is poorly understood. We show an oncogenic role for TRMT6 in CRC, revealing that TRMT6-mediated tRNA m¹A modification functions as a critical translational checkpoint that is essential for rapid histone synthesis in CRC cells.

Successful responses to chimeric antigen receptor (CAR) T cell therapy are limited in older patients. Compared with those from younger donors, CAR T cells generated from older donors had reduced stem-like properties, owing to mitochondrial defects associated with a decrease in nicotinamide adenine dinucleotide (NAD⁺) levels. Restoration of NAD⁺ levels reinstated mitochondrial fitness and rejuvenated the functionality of aged CAR T cells.

We built a repository of 124 tumor single-cell RNA-sequencing datasets and used it to systematically characterize the expression heterogeneity within tumors. These data and analyses together constitute the Curated Cancer Cell Atlas and are freely available for exploration and download via an enhanced online portal.

Esophageal adenocarcinoma (EAC) is challenging to treat because it frequently develops resistance to treatment. Multi-omic analyses of EAC during the course of treatment reveal phenotype plasticity of tumor cells and immune dynamics as mechanisms underlying therapy resistance that might have pharmacological relevance.

By tracking tumor antigens and tumor-reactive T cell clones in serial tumor and blood samples, we identify key mechanisms of resistance to tumor-infiltrating lymphocyte (TIL) therapy of lung cancer. Loss of antitumor reactivity and exhaustion by infused TILs was associated with therapy resistance. New tumors that emerged lacked the original antigens or tumor-reactive T cells, which suggests adaptive resistance.

A near-infrared optogenetic system was developed for the controlled expression of therapeutics in engineered oncolytic bacteria, demonstrating significant anti-tumor efficacy in multiple tumor mouse models. This approach offers a non-invasive, customizable method for targeted solid tumor therapy and has broader applications in engineered living therapeutics.

We took advantage of the multimeric structure and extraordinary antigen sensitivity of natural T cell receptors (TCRs) to engineer bispecific chimeric TCRs that may be more effective at treating cancer than traditional chimeric antigen receptor T cells. The dual-targeting approach helps to prevent relapses by addressing the variability among cancer cells in antigen expression.