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#肿瘤微环境

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Oct 15Thu
  1. biorxiv.org61

    A microbiota-driven neuroepithelial feed-forward circuit drives gastroesophageal junction tumorigenesis

    Bile acid remodeling enriches the oral commensal Prevotella melaninogenica at the gastroesophageal junction, where bacterial succinate activates vagal sensory neurons and SUCNR1-expressing tuft cells. Tuft cells release 15-d-PGJ2 to sensitize sensory neurons, while neuronal CGRP drives expansion and tuft-cell differentiation of neuro-responsive epithelial progenitors through RAMP1, forming a self-reinforcing microbiota-neuron-epithelium circuit that promotes dysplastic progression. Genetic or pharmacological disruption of the circuit, including with the approved CGRP antagonist rimegepant, suppresses tumor development.

Oct 14Wed
  1. biorxiv.org52

    Co-targeting KRAS and BCL-2 induces pyroptosis and antitumor tertiary lymphoid structures

    Co-targeting KRAS and BCL-2 synergistically triggers GSDME-mediated pyroptosis in KRAS G12D-mutant lung tumors, which are metabolically vulnerable through weakened HK1 interaction and reduced spare respiratory capacity compared with G12C. The combination induces functional tertiary lymphoid structures in vivo, and depletion experiments show the antitumor efficacy depends on B cells. It also drives membrane attack complex deposition in situ and elicits memory antitumor responses.

  2. biorxiv.org40

    Early-onset spontaneous murine mammary tumors show increased lymphocyte representation and reduced MHC antigen presentation

    A wild-derived PWK/PhJ genetic background accelerates HER2/neu-driven mammary tumor onset and reshapes the tumor immune microenvironment. (BALBxPWK) F1 NeuT females developed tumors at 10 weeks versus 15 weeks in BALB NeuT mice (p < 0.0001), with more tumor-infiltrating T and B cells but lower expression of cytotoxicity genes Tox, Ltk, Nkg7, and Gzmb. Proteomics found coordinate down-regulation of Stat1, Tapbp, Parp9, and Dtx3l with MHC class I and II proteins, indicating that inherited background, not the oncogene alone, governs antigen presentation and immune recognition in these tumors.

  3. biorxiv.org52

    Microglia-derived Small Extracellular Vesicles Promote Bone Marrow Monocyte Expansion and Recruitment in Glioblastoma.

    Tumor-associated microglia in glioblastoma release small extracellular vesicles that traffic to the bone marrow, where they selectively target monocytes and their progenitors. Internalization of these vesicles activates MAPK signaling and inflammatory transcriptional programs, driving differentiation and expansion of inflammatory monocytes that are then recruited into the tumor microenvironment. The work identifies a communication route between the glioblastoma TME and the peripheral immune system that helps establish the immunosuppressive TME driving GBM progression.

  4. biorxiv.org47

    Tumour-derived factors prime microglia for immune checkpoint-mediated T-cell regulation

    Soluble tumour-derived factors, not direct tumour contact, drive early microglial activation: quantitative proteomics showed extensive remodelling of the microglial proteome after exposure to tumour-conditioned media, with coordinated upregulation of MHC-I, PD-L1 and Galectin-9. Flow cytometry in murine and human cell models confirmed increased PD-L1 and MHC-I, and these microglia induced PD-1 and TIM-3 on cocultured T-cells. Single-cell RNA sequencing datasets from brain tumour patients recapitulate the same immune-regulatory program.

  5. biorxiv.org58

    Catabolism of extracellular glutathione is a driver of metastasis formation

    Cancer cells forming liver metastases can catabolize extracellular glutathione via gamma-glutamyl-transferase to obtain cysteine, sustaining proliferation and preventing ferroptosis when cystine is absent from the liver microenvironment. The mechanism was independent of system Xc- but required glutamate-cysteine ligase activity. GGT1 expression correlated with poor survival and was upregulated in liver metastases of human breast cancer patients, and Ggt1 overexpression in murine breast cancer cells enhanced liver colonization and lung metastases after orthotopic implantation.

    Why it matters: It identifies extracellular glutathione catabolism via GGT as a mechanism driving metastatic colonization of cystine-poor organs.

  6. biorxiv.org45

    Cyclic Hypoxia drives Wnt5a-ROR1 stroma-tumor crosstalk promoting breast cancer growth

    Cyclic hypoxia, unlike stable hypoxia, reprograms the triple-negative breast cancer microenvironment in a cell type specific way: it reverses chronic hypoxia-induced cell cycle arrest and a stabilized WNT5A+/COL6+ mesenchymal subpopulation, activates fibroblasts, and suppresses MSC proliferation. Single cell RNA and ATAC sequencing of a multicellular TNBC co-culture traced the effect to paracrine WNT5A/B-ROR1 signaling between fibroblasts and cancer cells. Blocking this crosstalk in a mouse CAF-TNBC co-xenograft model reduced tumor growth in vivo.

Oct 13Tue
  1. biorxiv.org51

    Spatial context of cellular heterogeneity in triple-negative breast cancer reveals actionable subtypes

    Bulk and spatial transcriptomics with cellular mapping of breast tissue from a large patient cohort identified three reproducible TNBC ecosystem subtypes with distinct spatial tumor-microenvironment architectures and treatment-response phenotypes: an immune-exhausted subtype associated with immune checkpoint therapy, a fibrotic/hypoxic subtype, and a metabolically reprogrammed subtype driven by nuclear-receptor and fatty-acid signaling. Multiplexed imaging independently confirmed the immune-infiltrated versus stromal-excluded architectures, and subtype-specific markers offer a basis for subtyping and candidate therapeutic vulnerabilities.

  2. biorxiv.org49

    Spatially resolved tumor-microenvironment architecture defines therapeutic response in unresectable hepatoblastoma

    Spatially organized tumor-microenvironment architecture distinguishes clinical outcomes in unresectable hepatoblastoma. Spatial transcriptomics (10x Visium, n = 11 tumors) and single-cell spatial imaging (NanoString CosMx, n = 3 tumors) on post-chemotherapy explants identified three architectures: relapse-prone tumors showed centralized, TME-dominated organization with SPP1+ TAMs, CAFs, hypoxia and MDK-LRP1 signaling, while non-relapse tumors showed compartmentalized tumor-immune interactions and preserved epithelial differentiation. Spatial architecture, not composition alone, may explain variable response beyond current risk stratification.

  3. biorxiv.org44

    Pan-cancer remodeling of reactive oxygen species homeostasis: distinct roles of the ROS-generation and antioxidant arms in immune context and outcome

    Pan-cancer analysis of a 107-gene ROS program shows both ROS-generation and antioxidant arms are coordinately up-regulated in tumors, but carry distinct meanings. The composite balance score tracked reduced immune infiltration, driven by low generation-arm activity in immune-cold tumors, while adverse outcome was attributable to the antioxidant arm and generation was null. In cohort-held-out validation, redox programs outperformed generic programs in separating tumors from adjacent normal tissue across cancer types.

  4. biorxiv.org50

    Malignant and stromal partial EMT programmes and cetuximab outcome in head and neck cancer

    Standard bulk partial EMT (pEMT) scores in head and neck squamous cell carcinoma mainly measure stroma: across three single-cell datasets, the malignant arm (laminin-332 and hemidesmosome genes) sat in malignant cells while the stromal arm (fibrillar collagens, vimentin) sat in fibroblasts. A classifier and 12-gene core recovering the malignant arm predicted long progression-free survival in 40 patients given platinum and cetuximab (AUC 0.78 and 0.82), but the malignant arm tracked the Basal subtype, whose score performed as well or better (0.93) and also in two xenograft panels.

    Why it matters: It shows bulk pEMT scores reflect stroma rather than tumour cells and that the Basal subtype score captures cetuximab outcome.

Oct 11Sun
  1. Sci Adv77

    Extracellular matrix-targeted TNC-scFv armoring enhances CAR T cell persistence and antitumor activity in solid tumors.

    Armoring CAR T cells with a secreted tenascin-C-targeted single-chain variable fragment (TNC-scFv) enhanced cytotoxicity, persistence, and reduced exhaustion in vitro and in xenograft tumor models. Single-cell transcriptomics showed the approach reprograms the tumor microenvironment toward a CD8+ T cell-enriched, functionally active immune landscape, and humanized tumor models showed robust antitumor responses with minimal systemic toxicity. Combining the armoring with interleukin-2 further increased efficacy while mitigating cytokine-associated toxicity, establishing extracellular matrix-directed armoring as a generalizable strategy for solid tumors.

    Why it matters: It offers a generalizable armoring strategy that improves CAR T cell function against solid tumors, where efficacy has been limited.

Oct 10Sat
  1. medicalxpress.com65

    Tracking molecular malfunctions in metastatic colorectal cancer to find new avenues for treatment

    Hokkaido University researchers, working with an international team led by University of South Florida Health and Tampa General Hospital, have shown that the 30-year-old sphingolipid rheostat model operates in the tumor microenvironment rather than inside cancer cells in metastatic colorectal cancer. Analysis of 574 human colon cancer tissue samples showed that rising sphingosine-1-phosphate and falling long-chain ceramide create a biochemical barrier that excludes cytotoxic T cells. In lab experiments, blocking S1P/S1PR3 let killer T cells attack tumors again, pointing to a combination strategy with immunotherapy.

    Why it matters: It explains a mechanism of immunotherapy resistance in metastatic colorectal cancer and identifies a druggable pathway.

  2. biorxiv.org40

    Proteomic Characterization of Prostate Cancer Bone Metastasis Subtypes Defines Progressive Remodeling States of the Bone-Tumor Microenvironment

    Proteomic profiling of lumbar vertebral specimens from 32 cadaveric prostate cancer bone metastases and 3 age-matched controls identified three clusters corresponding to benign, mixed, and osteosclerotic lesion states, each with distinct immune-, tumor-, and osteogenic-associated protein signatures. Tumor infiltration was accompanied by marrow fibrosis and increased collagen III deposition, and the protein markers reproduced similar groupings at RNA level in independent metastatic datasets, segregating bone from soft tissue metastases. The work defines molecularly distinct tumor-driven remodeling states that extend beyond histological classification and may guide biomarker and stratification efforts.

  3. biorxiv.org51

    A three-dimensional imaging pipeline for the detection of vasculogenic mimicry in mouse tumor models

    A 3D light-sheet imaging pipeline detects functionally perfused vasculogenic mimicry in mouse tumors, overcoming artifacts of 2D CD31/PAS staining that cannot confirm vessel function. Mice were injected with fluorescent tomato lectin, and tumors were optically cleared and stained with endothelial markers. Applied to six breast cancer patient-derived tissue xenograft models, an orthotopic mammary cancer model and two small cell lung cancer circulating-tumor-cell explant models, it revealed VM vessels, mosaic vessels and host-VM junctions.

Oct 9Fri
  1. biorxiv.org59

    The adaptive architecture of tRNA dependencies across physiological tumor environments

    tRNA dependencies are environmentally plastic and non-redundant, according to large-scale CRISPRi perturbation mapping across matched in vivo tumor growth and in vitro culture in 16 cancer cell lines from seven tissue types. In vivo, tRNA dependencies showed tissue organization at isodecoder resolution and linked to codon demand at the isoacceptor level, and these relationships reorganized in vitro, unlike aminoacyl-tRNA synthetase dependencies. A shared axis of isoacceptor dependency remodeling ties specific tRNAs to adaptation and to translation of codon-usage-biased programs for proliferation and tumor-microenvironmental stress.

  2. biorxiv.org53

    Behavioral dysfunction but not wasting in cancer cachexia is driven by altered tryptophan metabolism

    In mouse models of pancreatic cancer cachexia, tumors subvert tryptophan metabolism: serotonin is depleted while kynurenine accumulates in tumor, liver, muscle and spleen. Restoring serotonin activity, or blocking kynurenine production or kynurenine-mediated AhR activation, normalized feeding, locomotion and depression-like behavior, but did not change wasting, tumor burden or survival. The behavioral and feeding defects of cachexia are thus separable from its lethal systemic catabolism.

  3. biorxiv.org52

    Tumour-stroma signaling drives a reversible program with neural-like features in cancer-associated fibroblasts

    A NES+SOX4+NOTCH1+ neural-associated program in pancreatic cancer-associated fibroblasts is reversible rather than a fixed identity. Spatial transcriptomics from normal pancreas to invasive carcinoma identified EGF, FGF2 and BDNF as candidate tumor-to-fibroblast signals; EGF and FGF2 induced the program in patient-derived CAFs and fibroblast cell lines, and withdrawal reversed it at protein and transcriptional levels. MAPK/ERK signaling and ETS-family transcription factors drive the state, which pan-cancer single-cell analysis found enriched in CAFs across multiple cancer types.

  4. biorxiv.org43

    Inhibitory Nectin-2/TIGIT interactions between CD163+ macrophages and CD8+ T cells in spatially defined immune niches associate with poor outcomes in neuroblastoma

    CD163+ macrophages emerge as the dominant immunosuppressive interaction partner of T cells in neuroblastoma, engaging the TIGIT/PVR/Nectin-2 axis mainly at the tumor edge and in immune cores. Imaging mass cytometry (n=14) and spectral flow cytometry (n=18) on samples from 28 patients revealed T cell-excluded tumor niches and dysfunctional, tissue-resident T cells, with macrophage CD163 and Nectin-2 expression correlating with poor survival. The findings support combining strategies that boost T cell infiltration with blockade of inhibitory signaling.

Oct 8Thu
  1. Sci Adv65

    SLC39-driven zinc influx orchestrates pleiotropic tumor-immune system cross-talk to establish immune suppression in colorectal cancer.

    A zinc-CDX2-CD24-SIGLEC10 axis drives immune suppression in colorectal cancer, according to multi-omics analysis of 258 patients integrated with single-cell transcriptomics, spatial profiling and functional assays. SLC39-mediated zinc influx induced tumor cell CD24 expression, which reduced macrophage-mediated engulfment; CD24 blockade restored phagocytosis. A seven-gene signature predicted immunotherapy responses across five colorectal cancer cohorts.

  2. doi.org76

    Mechanotherapy enhances nanodrug uptake by overcoming the actin cytoskeleton damping effect

    Matrix stiffness in hepatocellular carcinoma suppresses nanoparticle uptake by driving F-actin polymerization and stress-fiber formation that mechanically damps the plasma membrane-actin interface. Tumor softening with β-aminopropionitrile reduced this mechanical resistance and improved NP penetration and cellular uptake. Combined softening with donafenib-loaded PLGA NPs cut endpoint tumor weight by 87.8% versus free donafenib, but increased pulmonary metastasis, exposing an efficacy-safety trade-off.

    Why it matters: Links matrix mechanics to nanodrug uptake at the membrane level and quantifies both the benefit and the metastasis risk.

Oct 7Wed
  1. biorxiv.org48

    RORγ Inverse Agonism Redirects Tumour-Conditioned Emergency Myelopoiesis and Attenuates Established Tumour Progression

    RORγ inverse agonism redirected tumour-conditioned emergency myelopoiesis and attenuated established tumour progression in syngeneic tumour models. In treatment-naive gastroesophageal adenocarcinoma patients, elevated circulating neutrophil-to-lymphocyte ratio tracked with circulating RORγ positive neutrophils and tumoural spatial organization of RORγ positive myeloid cells rather than neutrophil abundance. Pharmacologic RORγ inverse agonism altered marrow progenitor composition before tumour-growth divergence and enhanced longitudinal tumour control with PD-L1 blockade, with effects on metastatic establishment depending on tumour conditioning and treatment timing.

  2. Cell81

    Cancer competition for vitamin B2 creates metabolic checkpoint for T cell ferroptosis.

    Tumors use the transporter SLC52A2 to scavenge vitamin B2 and outcompete T cells, which depend on SLC52A3-mediated B2 uptake. Deprived T cells lose mitochondrial respiration and glutathione regeneration, undergo mitophagy, labile iron accumulation, and lipid peroxidation, and die by ferroptosis. Deleting tumor SLC52A2 restores T cell function in immunocompetent hosts, and B2 supplementation or SLC52A3 overexpression boosts CAR-T antitumor efficacy. High tumoral SLC52A2 correlated with T cell dysfunction and poor survival.

    Why it matters: It identifies a specific nutrient-competition mechanism causing T cell ferroptosis and a targetable transporter axis for immunotherapy.

Oct 6Tue
  1. biorxiv.org57

    A microbiota-dependent gut bile acid axis links germline mutant p53 to distal tumour growth.

    Germline mutant p53 reshapes the intestinal environment before tumours form: tumour-naive Trp53R172H/+ mice showed increased intestinal permeability, colonic inflammation with elevated NF-kappaB signalling, and altered bile acid metabolism, including higher levels of the microbiota-derived secondary bile acid deoxycholic acid (DCA), which correlated most strongly with distal tumour burden. Microbiota depletion reduced distal tumour growth and normalized the bile acid and inflammatory changes, while faecal filtrate transfer from mutant donors to wild-type recipients induced colonic inflammation and enhanced distal tumour growth. The work identifies a mutant p53-gut axis relevant to cancer predisposition in Li-Fraumeni Syndrome.

  2. biorxiv.org50

    Radiotherapy-induced vascular dysfunction alters neutrophil phenotype to promote tumor cell colonization of mammary adipose tissue

    Neutrophils drive circulating tumor cell colonization of irradiated mammary tissue in lymphocyte-deficient mice, a process that systemic neutrophil depletion abates. Neutrophils persist in the mammary tissue up to 10 days post-radiotherapy, acquire a PMN-MDSC-like phenotype induced by the RT-damaged microenvironment, and form an NF-kB-dependent positive feedback loop with irradiated endothelial cells that increases barrier permeability and vascular remodeling. The work identifies neutrophil-vascular crosstalk as a candidate target for preventing recurrence after radiotherapy in triple-negative breast cancer.

  3. biorxiv.org54

    RNA and protein are not interchangeable in single-cell spatial multi-omics

    Paired Xenium profiling of 21 matched RNA and protein targets across roughly 1.8 million cells from lung adenocarcinoma and metastatic castration-resistant prostate cancer shows the two modalities are not interchangeable. Lineage markers were concordant, but PD-1, PD-L1 and LAG-3 showed little agreement, and spatial organization was more discordant than overall abundance. The work sets rules for when spatial transcriptomics can proxy for protein and when orthogonal validation is needed.

  4. biorxiv.org52

    HMGA2 Expression in Pancreatic Ductal Adenocarcinoma Controls Tumor Microenvironment and Immunosuppression via IL1α

    HMGA2 expression marks basal-like pancreatic ductal adenocarcinoma cells and shapes an immunosuppressive tumor microenvironment. HMGA2 binds the IL1α promoter in tumor cells, raising IL1α levels, which polarizes fibroblasts toward immunosuppressive CAFs with IL6 and LRRC15 upregulation, increases regulatory T cells and reduces CD8+ T cells. Blocking IL1α signaling disrupts this phenotype and improves tumor control when combined with KRAS inhibitors.

  5. nature.com57

    Intestinal epithelial GSK3β governs fumarate-dependent neutrophil reprogramming to promote colorectal cancer

    In colorectal cancer cells, GSK3β phosphorylates H1FX, increasing glycolysis; the resulting fumarate accumulation in the tumor microenvironment comes via FH lactylation and drives neutrophils into an immunosuppressive phenotype through enhanced H3K36 dimethylation. The work links epithelial GSK3β to a metabolite-mediated route of neutrophil reprogramming that promotes colorectal cancer.

  6. biorxiv.org50

    Matched primary-metastasis single-nucleus and spatial profiling of leiomyosarcoma identifies antigen-presenting fibroblasts at the tumor-organ interface

    Matched primary and metastatic leiomyosarcoma samples reveal organ-specific malignant programs, with a stress- and hypoxia-associated program in lung metastases and a proliferative, matrix-remodeling program in liver metastases. Antigen-presenting cancer-associated fibroblasts were enriched in metastases (p = 0.001) and formed a band at the tumor-organ interface, unlike their sparse random distribution in primaries. Spatial profiling of 21 patients further defined three histomolecular phenotypes, including a GPNMB phenotype potentially targetable by GPNMB-directed therapies.

  7. biorxiv.org40

    Spatial transcriptomics reveals tumour cell-intrinsic and microenvironmental features associated with survival in high-grade serous ovarian carcinoma

    Spatial transcriptomics of 122 treatment-naive high-grade serous ovarian carcinomas, using a 480-gene panel, identified 61 tumour-intrinsic genes nominally associated with overall survival, with five linked to longer and nine to shorter survival. 46 of these 61 associations were lost when expression was aggregated across all cells, showing that whole-tissue profiling obscures tumour-cell-specific survival signals. Multiple tumour-proximal immune populations predicted longer survival, while two fibroblast populations predicted shorter survival. The findings resolve the cellular origins of bulk survival signatures in HGSOC and link tumour-intrinsic expression to the surrounding microenvironment.

  8. biorxiv.org49

    Mechanistic Decoding of Pharmacodynamic Intratumoral Heterogeneity: A Pan-Cancer Regulatory Framework

    A pan-cancer analysis links single-cell transcriptomes from 1,279 samples across 24 cancer types with drug-response profiles for 1,218 compounds, defining 425 hub genes associated with predicted treatment-response heterogeneity. A multi-omics case study in lung adenocarcinoma identifies four regulatory classes of candidate associations, including 3 transcription factors, 41 genomic alterations, 5 ligand-receptor pairs and 8 splicing genes, converging on 6 core tumor-intrinsic pathways. An online platform enables state-resolved drug-response analysis and candidate-gene exploration.

Oct 3Sat
  1. Sci Immunol53

    Multiomic analysis of malignant ascites defines RORC-expressing dendritic cells at sites of metastasis.

    Multiomic analysis of malignant ascites from patients with cancer identified RORC-expressing dendritic cells (RORC DCs) enriched at sites of peritoneal dissemination. These cells expressed PIGR, resembled murine RORγt+ dendritic cells and Thetis cells implicated in immune tolerance, and in vitro experiments with patient-derived RORC DCs showed they stimulated T cell proliferation while attenuating IFNG expression. Multiplexed immunofluorescence located RORC DCs in primary tumors and showed enrichment in regional lymph node metastases, linking them to advanced malignancy.

Oct 2Fri
  1. Nature66

    γδ T cell receptor dependencies define a unique immunosurveillance modality.

    The rapid, innate-like responses of tissue-intrinsic γδ T cells to tissue stress and carcinogenesis acutely depend on the γδ T cell receptor, contrary to reports that these responses are TCR-independent. The work shows that the immunosurveillance these cells mediate requires TCRγδ signalling, resolving uncertainty about whether tissue γδ T cells act through adaptive or innate mechanisms. Clinical deployment of these cells will evidently need environments supportive of TCRγδ signalling.

  2. Nature60

    Osteoclasts intercept meningeal lymphatic paths for dural metastasis.

    Cancer-related osteoclasts disrupt meningeal lymphatic drainage and drive dural metastasis in a new mouse model. Large osteoclasts cluster at the skull-tumour interface, smaller ones permeate tumour regions, and osteoclast-derived angiopoietin-2 dysregulates lymphatic drainage. Targeting osteoclasts restored lymphatic structure and function and strengthened anti-tumour immune responses.

  3. biorxiv.org58

    Clonally expanded CD8 T cells in AML adopt an NK-like program distinct from canonical exhaustion

    Clonally expanded CD8 T cells in newly diagnosed AML marrow are skewed toward terminally differentiated effector memory cells re-expressing CD45RA (TEMRAs), not canonical exhaustion, which was rare. In profiling 46 patients by mass cytometry plus single-cell RNA and TCR sequencing, most highly expanded clonotypes had unknown specificity and upregulated NK receptor-associated genes, defining a leukemia-associated NK-immune (LaNKi) score elevated in an independent AML dataset. This reframes AML T cell dysfunction as diverging from classical activation and exhaustion paradigms.

  4. biorxiv.org46

    A ncBAF to cBAF Switch Regulates Human Hematopoietic Progenitor Myeloid Differentiation

    Loss of the ncBAF subunit BRD9 in adult human hematopoietic stem and progenitor cells displaces ncBAF from chromatin and enhances cBAF recruitment to CEBPA target sites, skewing differentiation toward myeloid-derived suppressor cells that secrete elevated IL-8. Soluble factors from BRD9-deficient myeloid cells increased stemness of breast cancer cells in vitro. Bromodomain inhibition of BRD9, unlike degradation, minimally altered ncBAF binding and myeloid differentiation, showing BRD9 blocks MDSC differentiation independently of its bromodomain.

Oct 1Thu
  1. biorxiv.org64

    Early dynamics of a neutrophil interferon program drive immunotherapy resistance and limit durable anti-tumor immunity

    An interferon-stimulated gene program in neutrophils, detectable before tumors diverge in their response, predicts resistance to anti-PD1 therapy in preclinical triple-negative breast cancer models. Persistent neutrophil IFN signaling in blood and tumor tracked with treatment failure, while genetic disruption of type I or type II interferon signaling in neutrophils improved anti-PD1 efficacy and durable anti-tumor immune memory. The work positions IFN-responsive neutrophils as blood-based biomarkers and therapeutic targets.

    Why it matters: Identifies an early, blood-accessible neutrophil IFN signature that predicts anti-PD1 resistance and can be targeted.

  2. Cell64

    Spatial evolution of a cachexia-promoting microenvironment in pancreatic cancer.

    A defined multicellular niche in pancreatic tumors drives cachexia: SEMA4A+ tumor cells induce an AQP9+ macrophage phenotype via BMP2, macrophage-derived CXCL8 activates LOXL2+ fibroblasts, and those fibroblasts reinforce tumor FOSL1/SEMA4A signaling through exosomal N-glycosylated LOXL2. Integrating single-cell RNA sequencing, Xenium spatial transcriptomics, multiplex immunohistochemistry and functional studies in human samples and mouse models, the work shows the niche is progressively enriched with cachexia severity and predicts postoperative cachexia in previously non-cachectic patients. It supplies a spatially resolved circuit connecting the local tumor ecosystem to systemic wasting.

    Why it matters: It maps a spatially defined tumor niche that links pancreatic cancer progression to cachexia and its development.

  3. Oncoimmunology58

    A novel oncolytic peptide synergizing with immunotherapy

    Yuan et al. described in Nature an acid-responsive membranolytic peptide that separates lysosomal rupture from later plasma membrane rupture, turning oncolysis into immunogenic cell death. The design allows systemic administration, induces antigen-specific immunity and sensitizes tumors to programmed death ligand 1 blockade with limited toxicity.

    Why it matters: A preclinical Nature study shows an oncolytic peptide design that sensitizes tumors to PD-L1 blockade.

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