Fan et al. propose a non-genetically engineered, adoptive macrophage-based strategy via integrating anti-inflammatory (M2-like) macrophages with STING modulators to efficiently home to GBM and reshape the tumor immune microenvironment for improved therapeutic outcomes in mice models.

Hu et al. identify tumoricidal CD169+ macrophages in colorectal cancer (CRC) that directly target and kill CRC cells through CD169/CD43 interaction and FasL-driven apoptosis. This activity correlates with improved patient survival, revealing a new target for macrophage-based cancer immunotherapy.

Chai et al. reveal a mechanism linking energy metabolism to the inhibition of TBK1-induced type I IFN responses via the IRG1-itaconic acid axis and develop itaconic acid-based TBK1 inhibitors ITA-5 and ITA-9 as promising candidates for type I IFN-mediated hyperinflammation.

Fujimaki et al. used single-cell imaging and simulations to show that the DNA damage checkpoint system balances a tradeoff between reducing arrest failure from diploid cells and from damage-induced polyploid cells. Their study suggests that to minimize total arrest failure, checkpoint strengths need to be sub-optimal for each individual arrest-failure type.

Sun et al. use long-read sequencing data from high-grade serous ovarian cancer to perform de novo profiling of extrachromosomal DNA characteristics. They show that extrachromosomal DNA (ecDNA) is a multifunctional driver of genomic variations and tumor progression, including genomic instability, enhancer amplification, and transposon activation.

(Cell Reports 43, 113850; March 26, 2024)

Coagulase-negative staphylococci such as Staphylococcus haemolyticus are leading causes of blood infections. Quorum-sensing control in S. haemolyticus by the Agr system had a significant impact on the outcome of septic blood infection in mice, which was completely driven by production of phenol-soluble modulin toxins.

Newton et al. establish PERK as a copper-regulated kinase. The copper dependency of PERK kinase activity is characterized in vitro utilizing glutathione pull-down assays, kinase assays, and CETSA. The physiological implications of this regulatory paradigm for the modulation of ER stress tolerance are demonstrated in cellular and animal models.

González-Pérez et al. developed an in vitro method to induce trained immunity using murine bone-marrow-derived macrophages. Standardization of training protocols using experimental mouse models is critical for advancing our understanding of the mechanisms that regulate innate immune-memory responses and develop therapies that target trained macrophages under pathological conditions.

Ali et al. demonstrate that the neuropeptide ADM plays an important role in regulating GSC-macrophage symbiosis in GBM. EGFR-driven ADM promotes GSC self-renewal, macrophage infiltration, and pro-tumor reprogramming via the ADMR-STAT3/STAT6 pathway. Blocking this signaling axis disrupts the symbiosis and inhibits tumor growth in GBM mouse and PDX models.

Rominger et al. present a new autochthonous lung tumor model in which mutant RIT1 drives cancer together with p53 and Nf2 tumor suppressor gene loss. Transcriptomic and chromatin profiling shows that RIT1M90I promotes an EMT-like phenotype with high ZEB1 and AP-1 activity.

Korah, Reveron-Thornton, and Fallah et al. show that a subset of cancer-associated fibroblasts in PDAC use MYD88 signaling to suppress antitumor immunity and promote tumor growth. Combining MYD88 inhibition with immune checkpoint blockade mitigates these effects, revealing new insights into stromal regulation of the tumor immune microenvironment.

Gadek et al. show that embryonal rhabdomyosarcoma formation is defined by the presence of primary cilia and limits SHH pathway competency in early endothelial progenitor cells that disappear during embryonic development and differentiation. This potentially explains why rhabdomyosarcoma is the most common soft tissue sarcoma in children and is rare in adults.

Alkie et al. investigated the impacts of A(H5N1) from dairy cattle on other ruminants. The study shows that goats are highly susceptible to both bovine and avian strains, developing mastitis and shedding virus in milk and enabling transmission to offspring. Findings highlight the need for enhanced influenza surveillance in ruminant livestock.

Jung et al. discovered that the critical regulator of blood cell development, GATA2, suppresses the activity of transcriptional enhancers that activate genes encoding key regulators of inflammatory signaling. This GATA2-dependent process to prevent ectopic inflammatory signaling illustrates an important intersection between GATA transcription factor and inflammatory mechanisms.

Kim et al. show that colonization with a single E. coli strain limits microbiota-directed T cell inflammation. Colonization promotes CX3CR1+ APC IL-10 production, restricting colitogenic Th1 cell responses. This microbiota-driven circuit modulates intestinal T cell immunity to protect against colitis.

Lee, Biasini et al. define the composition and functions of the Integrator, NEXT, and nuclear exosome complexes in the Drosophila female germline. The study combines proteomics and multiple RNA sequencing-based approaches to catalog the molecular roles of these complexes in maintaining nuclear RNA homeostasis during fly germ cell development.

Li et al. show that hippocampal splitter cells implement a multiplexed neural code for contextual input and response and that parvalbumin neurons in the medial septum specifically modulates contextual representations supporting associative memory.

Microsporidia have the smallest eukaryotic genomes, with dramatically compacted proteins. Jiang et al. show that microsporidia proteins have lost domains and essential residues, resulting in functional degradation compared to their yeast counterparts, demonstrating how extreme genomic reduction impacts protein function.

Using optimized pupylation-based proximity labeling, Zhang et al. map the interactome of the E3 ligase complex GmAPC/C in soybean and identify the peroxisomal protein PEROXIN11C (GmPEX11C) as a substrate. GmAPC/C mediates GmPEX11C ubiquitination and degradation, revealing a mechanism by which this pathway regulates abiotic stress tolerance.

Wang et al. show β2AR as a methamphetamine target, with structural, behavioral, and synaptic plasticity studies revealing its distinct role from TAAR1 in addiction.

Carpentier et al. suggest that seipin regulates palmitate flux between sphingolipids and glycerolipids. Seipin loss causes ceramide buildup, trans-Golgi disorganization, and misrouting of caveolin-1 to lipid droplets instead of the plasma membrane. These findings identify seipin as a key regulator of overall lipid metabolism, protein trafficking, and organelle membrane homeostasis.

Immunotherapy with PD-1/PD-L1 checkpoint blockade (ICB) is effective in only a minority of cancer patients, suggesting that additional treatment strategies are needed. Peng et al. reveal a novel immune-suppressing mechanism mediated by the RSK-UBE2L6-RNF19A signaling axis and suggest a potential combination therapy strategy by combining ICB with RSK inhibition.

van der Net et al. show that mechanical interactions with the stromal component collagen I trigger reprogramming of colorectal cancer cells into a fetal-like state, through mechanosensitive integrins and calcium channels. These findings implicate mechanical forces in the regulation of stem cell plasticity during the metastatic cascade of colorectal cancer.

Li and Kumar et al. created strains expressing Chrimson in specific TRN subtypes and conducted high-throughput behavioral analysis after optogenetically activating them singly or in combination. They found that although the entire touch circuit integrates opposing stimuli linearly, this balance is lost if only part of the circuit is activated.