AbstractThe functional diversification of biosynthetic enzymes underlies the chemical richness of natural products, yet how primary metabolic enzymes evolve to acquire specialized functions in secondary metabolism remains elusive. Here, we report a tripartite enzyme complex from oral Streptococcus species—comprising 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase (HMGS), acetyl-CoA acetyltransfe...

AbstractBackgroundAccurately identifying functionally distinct tumor cell subpopulations remains a critical challenge in cancer research. While single-cell epigenomics assays provide powerful insights into tumor heterogeneity beyond gene expression, computational limitations have hindered their application.MethodsWe introduce Multimodal-based Analysis of scATAC-Seq data (MAAS), a method that in...

AbstractDecreased cross-presentation by antigen-presenting cells induces the scarcity of tumour-reactive T cells within the tumour bed, rendering in situ T cell rejuvenation through immunogenicity reprogramming highly desirable yet challenging1,2,3. Here we developed an intratumoural vaccination chimera (iVAC) to reprogram tumour cells into an antigen-presenting state (APC-like tumour cells) wi...

Graphical AbstractCancer-associated fibroblasts (CAFs) construct a protective stromal barrier that promotes tumor growth and resistance to therapy. To dismantle this, we developed CAT-BLAST, an engineered bacterial platform designed to potently eliminate these cells. We engineered a safe, high-expression E. coli chassis, arming it with a FAP-specific synthetic adhesin for precise CAF targeting ...

AbstractStress granules (SGs) are disease-relevant dynamic ribonucleoprotein condensates formed by liquid-liquid phase separation (LLPS) of proteins and mRNAs. Understanding their regulators and developing interventions are critical for therapeutic development. O-GlcNAc transferase (OGT) has been implicated in SG regulation, but functions beyond O-GlcNAcylation remain unclear. Here we uncover t...

AbstractThe cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS)–stimulator of interferon genes (STING) pathway has a crucial role in detecting tumour-derived DNA, whether the pathway is generated spontaneously or induced therapeutically. Activation of the cGAS–STING pathway triggers type I interferon signalling and pro-inflammatory responses in both tumour and immune cells...

AbstractThe clinical application of chimeric antigen receptor (CAR) T cell therapy in solid tumors remains limited due to significant safety concerns, particularly “on-target, off-tumor” toxicity and cytokine release syndrome (CRS). Here, we describe a class of CARs that employ disulfide-directed multicyclic peptides (DDMPs) as compact antigen-recognition domains targeting the tumor-associate...