Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) are generally resistant to targeted therapy with tyrosine kinase inhibitors (TKIs), such as imatinib, and there are no standard therapeutic options for advanced SDH-deficient GISTs. The precise oncogenic mechanisms of SDH mutations in GIST have not been elucidated. Olverembatinib, a novel multikinase inhibitor, has shown promising activity in treating imatinib-resistant GIST. We conducted a phase 1 study (NCT03594422) to evaluate the safety and antitumor activity of olverembatinib in 66 patients with unresectable/metastatic GIST/other solid tumors, including 26 with TKI-failed SDH-deficient GISTs. To our knowledge, this is the largest prospective clinical trial for this rare GIST subtype. The median follow-up was 14.5 (0.9–57.5) months. Olverembatinib was well tolerated; treatment-emergent adverse events (≥20%) included increases in hepatic transaminases, increases in leukocytes and neutrophils, anemia, and pyrexia. For SDH-deficient GISTs, confirmed partial responses were observed in 6 of the 26 evaluable patients (objective response rate, 23.1%; 95% CI, 9–43.7); an additional 16 (61.5%) did not progress during the first 6 months of treatment. This resulted in a clinical benefit rate of 84.6% (95% CI, 65.1–95.6), and the median progression-free survival was 25.7 months (95% CI, 12.9–NR). As a putative mechanism of action, translational research revealed significant lipid enrichment with the overexpression of lipid uptake-related genes and proteins, including CD36, fatty acid binding proteins, fatty acid transport proteins, and lipid metabolites, in SDH-deficient GIST patients, and olverembatinib suppressed lipid uptake and CD36 expression in GIST cells. Olverembatinib also exerts antitumor effects by inhibiting tumorigenic signaling pathways associated with hypoxia, angiogenesis, proliferation, and survival.

In a recent publication in Cell, Yang and colleagues propose a novel role for the serotonin transporter (SERT) as an immune checkpoint in CD8 + T cells. 1 These findings highlight the therapeutic potential of selective serotonin reuptake inhibitors (SSRIs) as anti-tumor drugs.Serotonin (5-hydroxytrptamine, 5-HT) is a monoamine transmitter with various important roles in the body, including in the immune system.5-HT signaling can promote immune cell migration and regulate cytokine production. 2 Immune cells express a diverse repertoire of 5-HT receptors (5-HTR) on their cell surface.While all immune cells respond to exogenous 5-HT, T lymphocytes (in particular CD8 + or cytotoxic T cells) also produce serotonin.Indeed, T cells possess the complete machinery for 5-HT synthesis, storage, degradation, and secretion. 3It has been demonstrated in vitro that during T-cell receptor (TCR) signaling, the synthesis and release of 5-HT increases. 2This leads to autocrine stimulation of 5-HTRs and enhanced T-cell activation. 2 Thus, serotonin appears to act as an accessory signal to help stimulate CD8 + T cells. 2,3Li et al. propose that SERT functions as a novel immune checkpoint in CD8 + T cells. 1 Checkpoints evolved as a homeostatic mechanism to constrain an overactive immune response.However, these signals can also be exploited (enhanced) by cancer cells to suppress immune function.Li et al. report upregulated SERT in tumor-infiltrating CD8 + T cells compared with nave cells, suggesting the tumor microenvironment alters T-cell serotonin signaling.Treatment with SSRIs, fluoxetine and citalopram, increased the number of intratumor CD8 + T cells and enhanced the cytotoxic functionality of these cells.Crucially, SSRI treatment also led to smaller tumor sizes and prolonged survival in both mouse syngeneic and human xenograft tumor models.SERT KO mice showed similar results as the SSRI treatments, supporting SERT as the SSRI target.Other cells, including cancer cells themselves, express SERT.Therefore, to identify a specific role for CD8 + T cells, Li et al. performed adoptive transfer experiments, transferring either normal or SERT-deficient immune systems/ CD8 + T cells into recipient mice with irradiated immune systems.Once again, disrupting SERT in these mouse models led to enhanced CD8 + T-cell function (less cell exhaustion and greater killing capacity) and a smaller tumor size.To identify a cellautonomous effect, they turned to cell culture experiments.In response to TCR stimulation, SERT KO CD8 + cells exhibited greater proliferation, cytokine generation, and cytotoxic function compared with wild-type CD8 + T cells.Similar results were obtained when wild-type CD8 + cells were stimulated in the presence of the SSRI, fluoxetine.

Despite the lack of predictive biomarkers and a prognostic stratification strategy, immune checkpoint inhibitor (ICI) has shown promise in improving outcomes for patients with limited-stage small cell lung cancer (LS-SCLC). We evaluated the potential of circulating tumor DNA (ctDNA) to dynamically predict outcomes in patients with LS-SCLC receiving concurrent chemoradiotherapy (CCRT) with or without consolidation ICI. We analyzed 490 serial samples collected from 144 LS-SCLC patients at baseline (t0), post-induction chemotherapy and pre-thoracic radiotherapy (t1), post-radiotherapy (t2), and progressive disease (t3). For 44 patients receiving consolidation ICI with serplulimab, an investigational PD-1 inhibitor, ctDNA dynamics during consolidation ICI were also assessed at multiple time points. Patients with undetectable ctDNA after CCRT had good outcomes with or without consolidation ICI, whereas ctDNA-positive patients at t2, indicating poor response to CCRT, derived survival benefit from consolidation ICI. Notably, ctDNA status at t1 appeared more predictive than at t2. A three-level risk stratification strategy integrating t1 ctDNA status with radiological tumor shrinkage identified a high-risk subgroup of patients who achieved significantly improved progression-free survival (PFS) (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.08–0.75; p = 0.014) and overall survival (OS) (HR, 0.06; 95% CI, 0.00–0.42; p = 0.001) from consolidation ICI, prioritizing CCRT plus consolidation ICI. Furthermore, maintaining ctDNA negativity during consolidation ICI was associated with favorable outcomes. These data provide valuable insights into the individualized management of LS-SCLC in the era of immunotherapy.

Castration-resistant prostate cancer demonstrates intrinsic or acquired resistance to second-generation androgen-targeted therapies, posing a challenge in clinical treatment. In this study, on the basis of in vivo self-assembly nanotechnology, we designed a PSMA-targeted nano-PROTAC with a proximity degradation effect. Nano-PROTAC not only precisely degrades the AR receptor but also cleverly degrades the HSP90 that is closely bound to the AR receptor, utilizing the spatial distance self-adaptive characteristics of its nanostructure. In the 22Rv1 cell model, Nano-PROTAC degraded 80% of the AR protein and 65% of the HSP90 protein. More importantly, nano-PROTAC could degrade 74% of the AR splice variant AR-V7 protein, showing the potential ability to overcome drug resistance. We further constructed an enzalutamide-resistant xenograft tumor mouse model to evaluate the therapeutic effect of the Nano-PROTAC. Compared with the combination treatment group of AR and HSP90 inhibitors (enzalutamide and pimitespib), the nano-PROTAC treatment group presented a high tumor growth inhibition value of up to 78% and a median survival extension of 15 days. Nano-PROTACs that simultaneously degrade AR and HSP90 can overcome the resistance of prostate cancer to PSMA- and AR-positive castration-resistant prostate cancer, except for neuroendocrine prostate cancer, which provides a new therapeutic strategy for the treatment of prostate cancer.

A recent study published by Zhang et al. 1 in Nature suggested that the endogenous ceramide receptors cysteinyl leukotriene receptor 2 (CYSLTR2) and the pyrimidinergic receptor P2Y6 (P2Y6R) are potential novel targets for the treatment of atherosclerosis and related cardiovascular conditions beyond mainstream cholesterol control strategies.This new finding paves the way for another milestone in the emerging innovative search for novel atherosclerosis therapies.Atherosclerosis is the leading cause of severe cardiovascular events such as myocardial infarction and stroke.Current drug treatment strategies focus primarily on lowering low-density lipoprotein cholesterol (LDL-C).Although statins and other lipidlowering medications reduce the risk of cardiovascular adverse events by approximately one-third, a significant number of patients still face "residual risk" and experience adverse cardiovascular events even when their lipid levels are within target ranges. 2This is particularly true for patients with chronic kidney disease (CKD), where the efficacy of cholesterol reduction in preventing cardiovascular diseases diminishes as renal function declines, nearly disappearing in patients with end-stage renal disease. 3New targets or strategies to combat atherosclerosis beyond cholesterol reduction are urgently needed.Ceramides are a class of sphingolipids formed by the linkage of sphingosine chains with fatty acid chains of varying lengths through amide bonds and signal via NOD-like receptor pyrin domain 3 (NLRP3) activation. 4A recent study via cryo-electron microscopy revealed that a Gi-coupled ceramide receptor acted through N-formyl peptide receptor 2 (FPR2) to regulate thermogenesis in adipocytes. 5Previous clinical studies have shown that long-chain ceramides in circulation, such as C16:0, C18:0, and C24:1, can predict the risk of cardiovascular events and are thus referred to as "second cholesterol."However, how long-chain ceramides in circulation exacerbate the development of atherosclerotic cardiovascular diseases and whether there are membrane receptors that mediate their pathogenic signaling have long been open questions in the scientific community.In this study, the authors identified for the first time a non-orphan endogenous membrane GPCR (G protein-coupled receptor) for circulating long-chain ceramides such as CYSLTR2 and P2RY6.Upon recognition of ceramides by these receptors, Gq protein activation is triggered, leading to activation of the NLRP3 inflammasome, which causes cleavage of caspase-1 (encoded by Casp1) and production of interleukin-1 (IL-1), both of which significantly exacerbate the

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and limited first-line treatments. This phase Ib/II randomized trial (NCT05218889) investigated the efficacy and safety of surufatinib plus camrelizumab and nab-paclitaxel/S-1 (NASCA) versus nab-paclitaxel and gemcitabine in patients with locally advanced or metastatic PDAC. The primary endpoints were dose-limiting toxicities and the recommended phase II dose (RP2D) of surufatinib in phase Ib, and the objective response rate (ORR) in phase II. Phase Ib used a 3 + 3 dose-escalation design to determine the RP2D of surufatinib in six patients, which was established at 200 mg. In phase II, patients were randomized 1:1 to receive the NASCA (45 patients) or nab-paclitaxel and gemcitabine (45 patients). NASCA group showed an ORR of 51.1% (23/45) versus 24.4% (11/45) in the nab-paclitaxel and gemcitabine group (odds ratio 3.2, 95% CI 1.3–8.2, p = 0.01). The median progression-free survival (PFS) was 7.9 vs. 5.3 months (HR 0.63, 95% CI 0.40–0.99, p = 0.045). The median overall survival was 13.0 vs. 11.0 months (HR 0.77, 95% CI 0.47–1.28, p = 0.318). The most common Grade ≥3 treatment-related adverse event was decreased neutrophil count (33.3% vs. 35.6%). In the NASCA group, enrichment of CD8+ and CD8+PD-1+ cells, a high baseline M1/M2 macrophage ratio, and a reduction in CA19-9 levels at weeks 6 and 12 were associated with improved PFS compared to patients without these features. The NASCA regimen showed promising efficacy with tolerable safety relative to nab-paclitaxel and gemcitabine for locally advanced or metastatic PDAC.

Lysophosphatidic acid (LPA) signaling has emerged as a central regulatory axis in both normal physiology and disease, orchestrating diverse cellular processes such as proliferation, survival, migration, immune modulation, and tissue remodeling. Originally identified as a bioactive lipid that regulates smooth muscle contraction and vascular tone, LPA has since emerged as a pleiotropic signaling molecule implicated in multiple physiological systems and a wide spectrum of pathological states. These include cancer, neurodegenerative disorders, cardiovascular and metabolic syndromes, inflammatory conditions, and fibrotic diseases. Elevated LPA levels, overexpression of autotaxin (ATX), and aberrant activation of LPA receptors (LPARs) contribute to disease initiation and progression, positioning the LPA axis as both a diagnostic biomarker and a promising therapeutic target. This review describes the multimodal and multinodal organization of the LPA signaling network, detailing upstream biosynthesis, receptor diversity, and downstream effectors across diverse organ systems. Therapeutic strategies targeting ATX, LPARs, and intracellular mediators are critically assessed, along with a review of ongoing and emerging clinical trials. Furthermore, we introduce a context-aware AI-based neural network model to simulate LPA signaling dynamics, providing a framework for predictive modeling and personalized therapeutic interventions. By integrating mechanistic insights with adaptive computational frameworks, this review positions the LPA axis as a powerful and versatile target for systems biology-guided precision medicine strategies in both health and disease.

Endothelial cells (ECs) form a critical bone marrow (BM) niche for hematopoietic stem cell regulation in homeostasis and stress states. However, BM ECs are frequently disrupted in hematologic diseases and their clinical interventions. Although transient EC injury is repairable, chronic activation of stress signals often induces maladaptive EC repair, which is a state of fibrotic reprogramming characterized by the loss of BM EC-specific functions and impaired hematopoietic-supporting ability. Although TGF-β1 (a pleiotropic cytokine) is implicated in angiogenesis and tissue repair, its role in driving BM EC maladaptation remains undefined. Here, in vitro experiments combined with a mouse model with adeno-associated virus-mediated BM EC-specific overexpression of constitutively active TGF-βRI demonstrated that TGF-β1 activation drives maladaptive BM ECs, characterized by defective vascular regeneration and impaired hematopoietic-supporting abilities. Multiomics profiling (transcriptomic and phosphoproteomic analyses) demonstrated a mechanistic link between maladaptive BM EC repair and a TGF-β1-induced secretome shift, characterized by the suppression of hematopoietic-supportive factors and the upregulation of epithelial-mesenchymal transition mediators. This effect may be driven by dysregulated vascular endothelial growth factor receptor/Notch crosstalk and subsequent p38α activation. Clinically, BM ECs from poor graft function (PGF) patients post-transplantation exhibited hyperactivated TGF-β1 signaling. In vitro experiments revealed TGF-β1 inhibition restored the function of maladaptive BM ECs from PGF patients. Subsequently, a prospective single-arm study involving luspatercept (a TGF-β ligand trap) demonstrated the significant promotion of multilineage hematopoiesis recovery in post-transplantation patients (NCT05629260). Therefore, our findings suggest that TGF-β1 may be a critical driver of BM EC maladaptation and highlight therapeutic TGF-β1 pathway inhibition for hematopoietic regeneration via BM EC remodeling.