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Aberrant deposition of ¦Â©\amyloid (A¦Â) and hyperphosphorylated tau, along with neuroinflammation, are key drivers of Alzheimer's disease (AD) pathology. Here, we identify ramalin, a natural antioxidant, as a promising therapeutic agent that alleviates AD pathology by modulating ¦Â©\site APP cleaving enzyme 1 (BACE1), histone deacetylase 6 (HDAC6), and the mitogen©\activated protein kinases (MAPK) pathway. Ramalin reduced BACE1 protein levels, independently of its transcription, translation, or enzymatic activity, an effect mediated by inhibition of HDAC6. Consistently, HDAC6 knockout similarly decreased BACE1 levels, highlighting HDAC6 as a key regulator of BACE1. Ramalin further suppressed neuroinflammatory responses by downregulating inducible nitric oxide synthase (iNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. In AD mouse models, ramalin treatment significantly attenuated neuroinflammation, A¦Â plaque burden, and tau hyperphosphorylation, while improving cognitive performance. Notably, ramalin reversed A¦Â oligomer©\induced synaptic transmission impairment and restored synaptic vesicle recycling in hippocampal neurons. Transcriptomic analysis identified modulation of the MAPK pathway, with reduced phosphorylation of c©\Jun N©\terminal kinase (JNK) and extracellular signal©\regulated kinase (ERK) implicated in tau pathology. These findings establish ramalin as a disease©\modifying intervention that provides neuroprotection through concurrent regulation of BACE1, HDAC6, and MAPK signaling pathway. Collectively, our findings highlight ramalin as a compelling disease©\modifying candidate with the potential to drive a breakthrough approach targeting AD pathology. Ramalin alleviates Alzheimer's disease pathology by selectively inhibiting HDAC6, reducing BACE1 levels, and suppressing neuroinflammation through downregulation of the NLRP3 inflammasome and iNOS. It restores synaptic function impaired by A¦Â toxicity and improves cognitive performance in AD mouse models, APP/PS1 and 3xTg©\AD. Additionally, ramalin modulates the MAPK signaling pathway, reducing tau phosphorylation by inhibiting JNK and ERK activation.

The immunomodulatory function of the gastric microbiota in cancer is poorly understood, partly due to the stomach¡¯s acidic environment and limited microbial colonization. Here, by analyzing 68 paired human gastric cancer (GC) samples, we identify Ligilactobacillus salivarius as a commensal bacterium depleted in tumors but enriched in immune checkpoint blockade (ICB) responders. Oral administration of L. salivarius enhances anti-PD-1 efficacy in multiple GC mouse models by promoting pro-inflammatory macrophage activation. Mechanistically, bacterial extracellular vesicles (bEVs) derived from L. salivarius deliver 2,3-bisphosphoglycerate-dependent phosphoglycerate mutase (2,3-BdpM) to tumors, where it activates formyl peptide receptor 1 (FPR1) on macrophages, triggering mitogen-activated protein kinase (MAPK) and nuclear factor ¦ÊB (NF-¦ÊB) signaling. Moreover, 2,3-BdpM augments the cytotoxic activity of chimeric antigen receptor (CAR)-Claudin18.2+ macrophages in an FPR1-dependent manner. These findings describe a microbial-macrophage axis that enhances GC immunotherapy and highlights the translational potential of orally deliverable microbial adjuvants. Graphical abstract Highlights?Intratumoral reduction of L. salivarius correlates with GC immunotherapy efficacy?bEVs derived from L. salivarius enhance immunotherapy efficacy in GC mouse models?2,3-BdpM in bEV triggers pro-inflammatory macrophage remodeling via FPR1?The cytotoxicity of CAR-Claudin18.2+ macrophages was amplified with 2,3-BdpM alone Yu et al. identify Ligilactobacillus salivarius as a gastric commensal enriched in immunotherapy responders. Oral administration enhances anti-PD-1 efficacy by delivering 2,3-bisphosphoglycerate-dependent phosphoglycerate mutase (2,3-BdpM) via bacterial extracellular vesicles (bEVs) to activate pro-inflammatory macrophages through formyl peptide receptor 1 (FPR1), revealing a microbial-macrophage axis that potentiates gastric cancer immunotherapy.

SummaryAlthough chimeric antigen receptor (CAR) T cells have demonstrated therapeutic activity in hematopoietic malignancies, tumor heterogeneity has impeded the efficacy of CAR T cells and their extension into successful solid tumor treatment. To address these challenges, induced pluripotent stem cell (iPSC)-derived T (iT) cells are engineered to uniformly express CAR and T cell receptor (TCR), enabling targeting of both surface and intracellular antigens, respectively, along with a high-affinity, non-cleavable variant of CD16a (hnCD16) to support antibody-dependent cellular cytotoxicity (ADCC) when combined with therapeutic antibodies. Co-expression of each antitumor strategy on engineered iT cells enables independent and antigen-specific targeting across a diverse set of liquid and solid tumors. In heterogeneous tumor models, coactivation of these modalities is required for measurable antitumor efficacy, with activation of all three modalities displaying maximal efficacy. These data highlight the therapeutic potential of an off-the-shelf engineered iPSC-derived trimodal T cell expressing CAR, TCR, and hnCD16 to combat difficult-to-treat heterogeneous tumors. Graphical abstract Highlights?CAR, TCR, and hnCD16 can be uniformly co-expressed and can function in iT cells?hnCD16 signals through CD3¦Æ and arms iT cells with targeting flexibility through ADCC?Concurring CAR, TCR, and hnCD16 activation demonstrates a cooperative effect?Multi-targeting with trimodal iT cells can control heterogeneous tumors in vivo Yang et al. show that (1) trimodal iPSC cells expressing CAR, TCR, and hnCD16 can commit to T cell lineage, (2) hnCD16 signals through CD3¦Æ in iT cells and arms iT cells with ADCC targeting flexibility, and (3) trimodal iT cells control antigen-heterogeneous tumors in vivo through multi-modal targeting.