In This Issue

Unlike metastatic colorectal cancer (mCRC) with microsatellite instability or mismatch repair (MMR) deficiency and subsequent high tumor mutation burden, microsatellite-stable and MMR-proficient mCRC is typically refractory to immune checkpoint blockade. As preclinical studies revealed that temozolomide (TMZ) leads to MMR deficiency and increased tumor mutation burden and subsequently sensitizes to immunotherapy, Crisafulli, Sartore-Bianchi, Lazzari, and colleagues initiated the ARETHUSA clinical trial in which patients with O6-methylguanine-DNA-methyltransferase (MGMT)–deficient, MMR-proficient, RAS-mutant mCRC were primed with TMZ prior to treatment with immunotherapy and demonstrate proof of concept that a TMZ-induced mutational signature and increased tumor mutational burden could be detected in tumor biopsies and blood following TMZ priming. Four of 6 patients treated to date with pembrolizumab after TMZ priming experienced disease stabilization.

See article, p. 1656.

EGFR exon 20 insertion mutations (EGFRexon20ins) account for approximately 2% of non–small cell lung cancer (NSCLC), with limited effective therapies. Wang and colleagues reported preclinical and clinical data of sunvozertinib, an irreversible and selective EGFR tyrosine kinase inhibitor, for treating EGFRexon20ins NSCLC. In both cell lines and xenograft models, sunvozertinib showed potent antitumor activity as well as demonstrated encouraging antitumor efficacy in patients with EGFRexon20ins NSCLC. The antitumor activity was found in a broad range of EGFRexon20ins subtypes, brain metastasis, as well as amivantamab treatment failures. The safety profile of sunvozertinib was clinically manageable. These data support further clinical development of sunvozertinib.

See article, p. 1676.

In a prospective study conducted by Zhang, Liu, Gao, Liu, and colleagues, 261 patients with stage I–IIIA non–small cell lung cancer (NSCLC) were enrolled after complete resection, with a total of 913 blood samples being successfully detected by molecular residual disease (MRD) assay. Six patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 96.8%, suggesting that corresponding undetectable MRD patients may not benefit from adjuvant therapy. Additionally, the peak risk of developing detectable MRD was approximately 18 months after landmark detection, thus patients with undetectable MRD 18 months after resection may have already been cured.

See article, p. 1690.

Metastatic colorectal cancer (CRC) shows limited responsiveness to therapies targeting adaptive and innate immunity, including IDO1 inhibitors. To identify key effectors in tumors with loss of APC, the initiating event of most CRC cases, Lee and colleagues employed the synthetic essential framework and revealed TCF4-induced upregulation of tryptophan 2,3-dioxygenase 2 (TDO2), which generates kynurenine to activate the aryl hydrocarbon receptor (AhR). AhR upregulates glycolysis genes and CXCL5, supporting cancer cell anabolic growth and the recruitment of suppressive tumor-associated macrophages, respectively. Inhibition of TDO2, but not IDO1, reduced tumor growth and increased survival only in the APC-mutant tumors, providing a novel therapeutic intervention for APC-mutant CRC.

See article, p. 1702.

Although immunotherapeutic approaches have been investigated for solid tumors, the overall response rate for hepatocellular carcinoma (HCC) remains modest. Hu, Yu, Ma, Sun, Liu, and colleagues explored the combination of IFNα and anti–PD-1-based immunotherapy, revealing that this strategy results in significant responses in both mice and patients. The CyTOF profiling revealed that the CD27⁺CD8⁺ T-cell population is enriched in the tumor microenvironment, and tumor-infiltrating CD27⁺CD8⁺ T cells have potential as a promising biomarker for stratifying patients for anti–PD-1 therapy.

See article, p. 1718.

Immune checkpoint therapies (ICT) revolutionized cancer treatment, but patient response rates remain low. Yuan and colleagues investigated whether common dietary supplements impact ICT responses through retrospective clinical studies and showed that patients taking vitamin E while receiving ICT had improved survival. Further mechanistic studies revealed that vitamin E enhances dendritic cell (DC) functions by directly binding to and inhibiting the SHP1 checkpoint in DCs, which leads to improved antigen presentation, T-cell priming, and more effective antitumor immunity. These findings suggest that vitamin E–treated or SHP1-silenced DCs and DC-derived extracellular vesicles could be developed as potent immunotherapies for clinical application.

See article, p. 1742.

Using genome-wide screens to identify dependencies in acute myeloid leukemia (AML) that are implicated in inflammatory signaling, Ellegast and colleagues identified the transcriptional repressor Interferon Regulatory Factor 2 Binding Protein 2 (IRF2BP2). Leveraging genetic and protein degradation approaches, loss of IRF2BP2 derepressed NF-κB signaling, through IL1β and TNFα, resulting in AML death. Knockout of IRF2BP2 reduced leukemia burden and prolonged survival in patient-derived xenograft models of AML but did not affect colony-forming capacity in normal human CD34⁺ bone marrow cells. This study validates IRF2BP2 as a candidate drug target in AML and uncovers the activation of cell-intrinsic inflammation as a therapeutic strategy.

See article, p. 1760.

Homozygous deletion of SETD2, which encodes the only histone methyltransferase that can trimethylate H3K36, occurs across multiple tumor types and leads to defective DNA damage repair and transcription, suggesting a role for SETD2 as a tumor suppressor. However, SETD2 mutations in diffuse large B-cell lymphoma (DLBCL) are typically heterozygous without loss of heterozygosity for reasons that are unclear. Leung and colleagues showed that heterozygous deficiency of Setd2 caused hyperplasia of the germinal center and decreased apoptosis leading to enhanced lymphomagenesis. Furthermore, these cells demonstrated somatic hypermutation induced by activation induced cytosine deaminase (AICDA) contributing to genomic instability, including translocation at the Myc locus. Overall, these results suggest therapeutic potential for targeting the SETD2 dependency of DLBCL cells.

See article, p. 1782.

Gastrointestinal stromal tumor (GIST) relies upon epigenetic regulation of mutant KIT gene expression to drive tumorigenesis. Tyrosine kinase inhibitors are the only approved therapy for GIST, and complementary treatment strategies are needed. Hemming and colleagues performed a genome-scale CRISPR dependency screening in GIST, identifying complementary regulation of the GIST epigenome by Menin–MLL and MOZ complexes. These complexes were found to regulate core GIST transcriptional programs and chromatin association of key epigenetic regulators. Their inhibition reduced GIST growth in vitro and in vivo, with superior effects seen in combination with KIT inhibition, establishing a novel treatment strategy for GIST.

See article, p. 1804.