Multimodal artificial intelligence, albeit showing great potential in computational pathology, remains limited to isolated patch-level interpretation and often fails to analyze gigapixel-scale whole-slide images (WSIs) essential for clinical utility. Here we present SlideChat, a multimodal generative artificial intelligence assistant for whole-slide computational pathology across cancer types. SlideChat integrates patch-level and slide-level pathology encoders with a pretrained large language model. Using 274,233 multimodal instruction samples, SlideChat is trained to learn the associations between WSIs and diagnostic reports and interpret complex queries in clinical practice. Evaluated on 8,836 closed-ended questions, 129 open-ended questions and 3,149 WSI reports from five cohorts spanning 31 cancer types, SlideChat outperformed leading baselines by 19.1% in closed-ended accuracy and by 7.7% in report-generation Metric for Evaluation of Translation with Explicit Ordering score and received the highest expert ratings across five dimensions in open-ended question answering, showing the potential to enhance diagnostic workflows, medical education and clinical decision-making.
Exogenous L-glutamine has preclinical antitumor activity although formal clinical translation has not been attempted. We conducted a single-arm phase 1 trial to assess the safety and preliminary efficacy of clinical-grade, US Food and Drug Administration-approved L-glutamine therapy with gemcitabine and nab-paclitaxel (GA) in participants with treatment-naive, advanced pancreatic cancer (n = 16). The primary endpoint was to determine the recommended phase 2 dose (RP2D) by adaptive Bayesian design across standard doses of GA and a dose range of 0.1-0.3 g kg-1 twice-daily oral L-glutamine. Secondary endpoints included safety and preliminary efficacy of the study combination. The primary endpoint was met with the RP2D reached at maximum doses of L-glutamine and GA. The grade ≥3 treatment-related adverse event rate was 66.7%, primarily from GA. Addition of L-glutamine to GA induced tumor shrinkage in 94% of subjects with a best overall response rate (ORR) of 44% (12.5% complete response). Median progression-free survival and overall survival (OS) were 8.5 months (95% confidence interval (CI) 6-not reached (NR)) and 22 months (95% CI 11-NR), respectively. L-Glutamine induced distinct metagenomic and metabolomic signatures on exploratory analyses in glutamine-treated subjects as a single agent, while the combination of L-glutamine and GA nearly doubled the ORR and tripled the OS compared to historical GA alone (ClinicalTrials.gov registration: NCT04634539 ).
Regulatory T (Treg) cells prevent autoimmune diseases but limit antitumor immunity. Tumor‑infiltrating Treg (Ti‑Treg) cells exhibit metabolic traits as potential antitumor targets. Here, we find that Ti-Treg cells upregulate glutamate dehydrogenase 1 (GDH1), increasing α-ketoglutarate (α-KG) levels. Elevated GDH1 in Ti-Treg cells accelerates tumor progression. Mechanistically, in a lactate rich microenvironment, GDH1 lactylation boosts α-KG production to fuel ALKBH5-mediated Wnt2 expression in Ti-Treg cells. Enhanced WNT2 promotes natural killer (NK) cell senescence. GDH1 inhibition or SLC16A1 deletion in Ti-Treg cells reduces NK senescence and improves adoptive NK transfer therapy. We reveal a lactate-α‑KG metabolic circuit driving NK senescence, offering therapeutic targets to boost antitumor immunity.
Dietary interventions can influence cancer progression, yet the role of low-protein diets (LPDs) in pancreatic ductal adenocarcinoma (PDAC) immunotherapy is unclear. Here we show that an LPD suppresses PDAC progression in male mice by remodeling the gut microbiota and activating antitumor immunity. LPD promoted immune activation and drove an immunostimulatory tumor-associated macrophage phenotype. Microbiota depletion abolished these effects and fecal microbiota transplantation from LPD-fed donors transferred the protective phenotype to recipients. Mechanistically, LPD enriched Blautia coccoides, which produced uridine diphosphate (UDP)-galactose to activate the macrophage P2Y14R-STAT1 axis, inducing an immunostimulatory phenotype. Combining LPD, B. coccoides or UDP-galactose with anti-PD1 improved survival over anti-PD1 alone. In persons with advanced PDAC, reduced fecal B. coccoides and serum UDP-galactose correlated with poor outcomes. These findings establish that LPD reshapes the gut microbiota and metabolites to enhance antitumor immunity through the UDP-galactose-P2Y14R-STAT1 axis, offering a dietary strategy to improve PDAC immunotherapy.
Acute myeloid leukemia (AML) remains challenging, especially for older or unfit individuals who develop resistance to venetoclax (VEN)-based regimens. Although TIM3 represents a promising AML target, clinical blockade has yielded suboptimal outcomes. Here, we develop VINCENT (VEN-integrated natural killer cell engager targeting TIM3), a therapeutic platform combining anti-CD16 and anti-TIM3 antibodies with nanoformulated VEN. In VEN-resistant AML cell lines and patient-derived xenograft models, VINCENT overcomes resistance by enhancing VEN delivery, eliminating TIM3+ blasts and dysfunctional T cells and activating natural killer (NK) cells. In primary AML samples, VINCENT selectively kills drug-resistant blasts, with efficacy correlating with the NK cell-to-TIM3+ blast ratio. Single-cell transcriptomics reveals VINCENT depletes high-TIM3 blasts and remodels the immunosuppressive microenvironment toward immune competence. Collectively, VINCENT simultaneously addresses VEN resistance, NK cell dysfunction and immune evasion, offering a personalized option for elderly or unfit individuals with AML failing standard VEN regimens.
Intratumor heterogeneity poses a fundamental challenge across the cancer care continuum, from diagnosis to treatment resistance and metastasis. Over recent decades, multiregion and multiomic profiling of tissue, together with functional studies and longitudinal plasma sampling, have revealed the dynamic and multidimensional evolution of tumor ecosystems. This complexity spans genetic and non-genetic mechanisms within cancer cells and their microenvironment. In this Review, we synthesize the current understanding of heterogeneity and evolution and discuss how these insights can inform the development of evolution-aware diagnostic and therapeutic strategies.
The mechanisms by which tumor-derived extracellular vesicles and particles (EVPs) promote vascular permeability during premetastatic niche formation remain unclear. Here, we show that tumor EVPs rapidly induce vascular leakiness within 1 h of administration in female mice, creating a permissive environment that enhances metastatic seeding. Rather than acting directly on endothelial cells, EVPs activate NF-κB and JAK-STAT signaling in interstitial macrophages, leading to IL-6 secretion and increased vascular permeability. Interstitial macrophage depletion markedly reduces EVP-induced vascular leakiness and metastasis. We identify extracellular vesicle-associated integrin α5 (ITGα5) as a major functional determinant of this process, promoting macrophage activation and IL-6 secretion without affecting EVP uptake. EVPs derived from colorectal cancer tumors with high ITGα5 similarly induce macrophage IL-6 secretion and vascular permeability. Together, these findings define an EVP-macrophage-IL-6 axis that drives vascular permeability during premetastatic niche formation and identify EVP-associated ITGα5 as a key mediator of metastatic progression and a potential therapeutic target.
Targeting the stimulatory immune checkpoint glucocorticoid-induced TNFR-related protein (GITR) using agonistic monoclonal antibodies (mAbs) is a promising strategy for cancer immunotherapy that activates effector T cells and eliminates regulatory T cells. The antitumor activity of anti-GITR mAbs depends on the engagement of the fragment crystallizable (Fc) domain to their receptors (FcγRs); however, this has not been comprehensively investigated in human anti-GITR mAbs. Here, we used Fc protein and glycan engineering to modify the FcγR interactions of anti-GITR human mAbs and characterized them in humanized mice. We identified an Fc-optimized human IgG scaffold that enhances antitumor efficacy through multiple FcγR-mediated mechanisms, including regulatory T cell depletion and mutual engagement and activation of CD4+ T cells and dendritic cells, leading to antitumor cytotoxicity of CD4+ T cells and enhanced CD8+ T cell activity. Our findings suggest a strategy to optimize human anti-GITR mAbs, harnessing beneficial immune pathways to improve their therapeutic potential.
The latest ESMO Targeted Anticancer Therapies Asia Congress brought together researchers, clinicians and industry experts to discuss how advances in molecular oncology, cell therapies, artificial intelligence and translational science are shaping the next generation of cancer treatments. Opening the meeting, European Society For Medical Oncology (ESMO) president Fabrice André highlighted the society’s increasing global reach, with members spanning Europe, Asia and other regions worldwide. He emphasized the ESMO’s mission to support oncology professionals through education, consensus frameworks and clinical guidance while outlining the 2030 strategic priorities, including innovation in cancer treatment, real-world impact, prevention, survivorship and professional development.
Despite their crucial roles in physiology, the contributions of trace metals to cancer fitness and therapy response remain unclear. Combining a CRISPR screen with functional and metabolic studies, recent work identifies copper homeostasis as a key regulator of mitochondrial metabolism and liability in cerebrospinal fluid-infiltrating acute lymphoblastic leukemia cells.
Visceral crisis in advanced breast cancer (ABC) represents a major challenge. Here we conducted a phase 2 study to evaluate dalpiciclib plus endocrine therapy (ET) in women with HR+/HER2- ABC experiencing visceral crisis. The primary endpoint was the 6-month survival rate; secondary endpoints included overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), 3-month treatment failure rate (TFR), duration of disease control (DDC), objective response rate (ORR), disease control rate (DCR) and safety. Among 53 participants, 49 survived beyond 6 months, yielding a 6-month survival rate of 92.5% (95% confidence interval (CI): 81.8-97.9), meeting the primary endpoint. The ORR was 26.4%, DCR was 79.2% and 3-month TFR was 22.6%. The median PFS was 11.2 months (95% CI: 7.6-19.3), DDC was 14.1 months (95% CI: 8.4-21.5) and TTF was 10.2 months (95% CI: 6.4-15.6); the median OS was not reached. The most common grade ≥3 adverse events were neutrophil count decreased (77.4%) and white blood cell count decreased (54.7%). Exploratory analyses indicated that a baseline monocyte-derived cfDNA level below 0.0581 was associated with worse OS (hazard ratio: 4.79, 95% CI: 1.05-45.47, P = 0.0394), indicating a 'molecular crisis'. These findings support further evaluation of dalpiciclib plus ET in persons with ABC with visceral crisis (ClinicalTrials.gov: NCT05431504 ).
Polyadenylation is essential for mRNA stability and translational efficiency. Although poly(A) tail length is dynamically regulated under physiological conditions, its dysregulation and functional importance in cancer remain poorly understood. Here, we identify widespread poly(A) tail elongation and aberrant upregulation of poly(A) polymerase alpha (PAPOLA) in acute myeloid leukemia (AML), with high PAPOLA expression associated with poor clinical outcomes. Using primary AML samples, leukemia cell lines and multiple mouse models, we demonstrate that PAPOLA-driven hyperactive polyadenylation promotes leukemogenesis and sustains leukemia stem cell maintenance. Mechanistically, PAPOLA enhances metabolic reprogramming by upregulating glutathione S-transferase mu 2 (GSTM2), which activates the 4-hydroxynonenal (HNE)-dihydrolipoamide dehydrogenase (DLD) axis to drive AML progression. Notably, pharmacological inhibition of PAPOLA with cordycepin suppresses metabolic reprogramming and impairs leukemogenesis. Overall, our findings establish hyperactive polyadenylation as a core oncogenic mechanism linking RNA processing to cancer metabolism in AML, highlighting the PAPOLA-GSTM2-HNE-DLD axis as a promising therapeutic target.
Aberrant glycosylation is a nearly universal hallmark of cancer cells. Tumor-associated glycans can reshape cancer cell biology and act as crucial suppressors of anti-tumor immunity. By engaging immune inhibitory receptors or by modifying the function of immune checkpoints, glycans dampen natural immune responses and immunotherapy efficacy. Therefore, glycans serve both as direct targets for anticancer interventions and as adjuvants aimed at potentiating immunotherapy success. In this Review, we provide an overview of tumor glycosylation and its impact on cancer immune surveillance. Finally, we discuss recent therapeutic developments that highlight the potential of glycans as precision cancer medicines.
