Highlighted research articles

Cell-free DNA (cfDNA) concentrations in patients with cancer are often elevated. Mattox and colleagues sought to determine the source of this extra DNA by assessing cfDNA methylation patterns in 178 patients with cancers of the colon, pancreas, lung, or ovary as well as 64 patients without cancer. Leukocytes were found to contribute to the majority of cfDNA in nearly all samples regardless of total cfDNA concentration. The high levels of cfDNA observed in patients with cancer did not generally arise from neoplastic cells or from surrounding epithelial cells within the tumor. These data suggest that cancers may have a systemic effect on cell turnover or DNA clearance.

See article, p. 2166.

Breast cancer diagnosed postpartum (PPBC) is a malignancy with a poor prognosis that lacks effective screening protocols. In this study, Saura, Ortiz, and colleagues demonstrated the presence of cell-free tumor DNA (ctDNA) in the breast milk (BM) of patients with breast cancer, showing superior sensitivity compared to plasma liquid biopsy. The analysis of BM ctDNA was feasible even at very early stages of the disease, with examples illustrating detection prior to standard diagnosis by imaging. BM also accurately recapitulated the genomic profile of the tumor. Collectively, these findings suggest the future evaluation of BM genotyping as a scalable screening method for the early diagnosis of PPBC.

See article, p. 2180.

The tumor microenvironment is instrumental for prognosis and therapy response of colorectal cancer. In this study, Farin and colleagues established a biobank comprised of tumor organoids and matched cancer-associated fibroblasts from 30 patients with colorectal cancer that serves as a preclinical tool for more accurate prediction of therapy response. Molecular analyses showed that the tumor subtype strictly depends on the stromal context, while pharmacotyping of clinical drugs revealed individualized effects of cocultures on therapy responses. Drug screening in resistant models provided mechanistic insights and enabled identification of combinatorial treatment strategies, thus rendering this biobank a valuable resource to study stroma-induced tumor phenotypes.

See article, p. 2192.

In an effort to dissect the mechanisms of response to dual neoadjuvant anti–PD-1 and anti-CTLA4 therapy, van der Leun, Traets, and colleagues analyzed tumor immune infiltrates from both responding and nonresponding patients with head and neck squamous cell carcinoma and showed that a higher ratio of active to inactive regulatory T cells (Treg) at baseline was associated with immunotherapy response. Moreover, the active Treg population was reduced upon treatment in responders, with a parallel reduction in intratumoral dysfunctional CD8⁺ T cells that exhibit hallmarks of activation also being observed. Together, these results reveal a parallel immunologic remodeling in response to dual immune checkpoint inhibitor treatment.

See article, p. 2212.

Enhancing antitumor immunity remains a goal in the management of cancer. In this study, Guirguis, Ofir-Rosenfeld, and colleagues demonstrated the utility of inhibiting the catalytic activity of METTL3, the key writer of m6A on mRNA, as an anticancer immunotherapy. METTL3 inhibition resulted in a cell-intrinsic interferon response mediated by formation of double-stranded RNA and augmented antitumor killing as a single agent. Moreover, inhibition of METTL3 synergized with anti–PD-1 in several preclinical tumor models. These findings provide the molecular and preclinical rationale to underpin clinical translation of METTL3 inhibitors as a novel immunotherapeutic approach.

See article, p. 2228.

KRAS mutations are causally linked to protumor inflammation and identified as driving factors in tumorigenesis. Zhang, Huang, Pan, Sang, and colleagues comprehensively profiled the alternative splicing landscape in intrahepatic cholangiocarcinoma (iCCA) using high-throughput datasets containing 496 samples and identified a negative feedback mechanism mediated by KRAS-related mRNA splicing of IL1RN, which, in turn, plays an anti-inflammatory role in suppressing KRAS-mutant iCCA. This negative feedback mechanism promotes the formation of antitumor immunologic hubs in KRAS-mutant iCCA through the regulation of neutrophil recruitment, function, and phenotype, resulting in a tumor microenvironment responsive to anti–PD-1 therapy.

See article, p. 2248.

Patients with melanoma harbor mutations in oncogenes such as BRAF and NRAS, but it remains to be understood which microenvironmental factors determine the ability of oncogenes to cause cancer. Tagore and colleagues showed that nascent tumor cells actively communicate with the stromal microenvironment in melanoma through GABA, a neurotransmitter produced by tumor cells. GABA interacts with GABA-A receptors on keratinocytes, and this interaction results in the dampening of electrical activity in the skin microenvironment. Moreover, GABA production was shown to be protumorigenic in zebrafish, mouse, and human 3D skin reconstruct melanoma models, which highlights the significance of this pathway and suggests GABA as a potential new therapeutic target in the melanoma microenvironment.

See article, p. 2270.