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Oct 15Thu
  1. Nat Biotechnol69

    Mesenchymal thymic niche cells enable regeneration of the adult thymus and T cell immunity.

    A perivascular Postn+ mesenchymal subset of thymic stroma, identified by single-cell analysis of human and mouse tissue, proved to be a critical niche for T lymphopoiesis. Depleting these cells, which likely produce the chemokine Ccl19, blocks recruitment of T cell progenitors, and the subset declines with age and after hematopoietic stem cell transplant conditioning. Adoptively transferred Postn+ cells durably engraft the atrophic thymus, recruit early T progenitors, increase T cell neogenesis and improve T cell responses to vaccination; Ccl19-expressing mesenchymal populations give similar effects.

  2. Nat Biotechnol69

    Engineering bispecific exosome activators of T cells to target immune checkpoint inhibitor-resistant metastatic melanoma.

    An inhalable exosome system called BEAT co-displays PD-1 and FZD8 in a uniform 1:1 ratio to block PD-L1 and Wnt7b, overexpressed in immune checkpoint inhibitor-resistant melanoma. BEAT recruited and activated CD8+ T cells, reprogramming the tumor microenvironment and producing robust antitumor activity in mouse models of lung metastases, outperforming a linked dual antibody against PD-L1 and Wnt7b in vivo.

Oct 14Wed
  1. nature.com50

    Personalized neoantigen-targeting cancer vaccines in ovarian cancer: a phase 1 trial

    Personalized neoantigen vaccines combined with PD-1 blockade were feasible in patients with high-grade serous ovarian cancer in a phase 1 trial. Many patients mounted tumor-specific immune responses. Cell-free DNA analysis identified putative resistance mechanisms related to antigen presentation. The trial establishes feasibility of this approach in ovarian cancer and points to antigen presentation as a resistance pathway.

  2. 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.

  3. biorxiv.org53

    FLASH X-rays preserve neutrophil chromatin to boost antitumor immunity

    FLASH X-rays at 8 Gy, unlike an equal conventional dose-rate dose, triggered a robust abscopal antitumor effect with anti-PD-1 in a bilateral subcutaneous tumor model in mice. The ultrashort dose delivery conserved neutrophil chromatin compaction, inhibiting neutrophil extracellular trap formation and reversing NET-mediated CD8+ T-cell exclusion, while conventional or split-dose FLASH caused chromatin hyper-relaxation and NETosis. Radiation-induced chromatin relaxation in neutrophils emerges as a determinant of radioimmunotherapy outcome.

Oct 13Tue
Oct 11Sun
  1. doi.org75

    Topological Engineering of NIR-II Emissive Conjugated Oligomers With Unexpected Excited-State Manifolds for Efficient Phototheranostics and Cancer Immunotherapy

    Topology-driven excited-state engineering of conjugated oligomers yields nanoparticles that improve both imaging and therapy. Under 808 nm laser irradiation, TBT-3 nanoparticles showed 2.8-fold enhanced NIR-II fluorescence brightness, 2.7-fold improved photothermal performance, and 7.5-fold increased total ROS generation versus TBT-1. In vivo, TBT-3 nanoparticles enabled high-resolution NIR-II fluorescence imaging and tumor elimination, and phototherapy induced immunogenic cell death, improving efficacy combined with anti-PD-1 blockade.

    Why it matters: It links a molecular topology strategy to quantitative gains in NIR-II imaging and phototherapy plus anti-PD-1 synergy.

  2. 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. Nat Med62

    Extended follow-up of in vivo BCMA CAR-T therapy in relapsed/refractory multiple myeloma.

    Extended follow-up of in vivo BCMA CAR-T (ESO-T01), given without leukapheresis or lymphodepletion to four patients with relapsed/refractory multiple myeloma, shows no new important adverse events beyond the initial report at up to 15 months. One patient maintained stringent complete response for 15 months; median progression-free survival was 4.0 months (range 3.0-15.0). Three patients relapsed or progressed, all with extramedullary involvement, and died during follow-up, indicating limited CAR-T persistence requiring platform optimization.

  2. biorxiv.org58

    NECTIN4 defines a subtype-dependent tumor state coupling enfortumab vedotin targetability to antitumor immunity in bladder cancer

    NECTIN4, the target of enfortumab vedotin (EV), acts as a subtype-dependent determinant of tumor state and antitumor immunity in bladder cancer. Integrating clinical multi-omics, spatial and single-cell immune profiling, and experimental models, the work shows NECTIN4-high basal/squamous muscle-invasive tumors had favorable survival, higher checkpoint inhibitor response rates, and a CD8+ T cell-inflamed microenvironment, with no comparable associations in luminal papillary tumors; NECTIN4-low models were preferentially sensitive to HDAC inhibition.

Oct 9Fri
  1. biorxiv.org55

    Neutrophils orchestrate pre-metastatic immunosuppressive bone marrow remodeling during prostate cancer metastasis

    Tumor-associated neutrophils drive pre-metastatic immunosuppressive bone marrow remodeling in prostate cancer, emerging at the high-risk bone metastatic potential stage and correlating with poor patient prognosis. Tumor-associated systemic IGF1 reprograms marrow neutrophils via IGF1R-MAPK/ERK-KLF4 signaling, and Igf1 perturbation, IGF1R blockade or neutrophil-specific Igf1r deletion reduces bone metastatic progression. An investigator-initiated trial of teprotumumab plus tislelizumab in metastatic castration-resistant prostate cancer provided initial safety data.

  2. doi.org74

    IGF2BP1 in 17q-gain cooperates with MYCN to regulate purine biosynthesis and immunotherapy efficacy in neuroblastoma

    A CRISPR screen of 17q-gain genes identified the RNA m6A reader IGF2BP1 as a critical MYCN collaborator in aggressive neuroblastoma, acting through activation of PAICS, a key enzyme in de novo purine biosynthesis. PAICS-mediated nucleotide metabolism sustained purine pools for transcription of replicative stress-responsive genes including CHK1. Pharmacological inhibition of CHK1 activated cGAS-STING signaling, upregulated MHC class I expression, and suppressed tumors synergistically with immune checkpoint blockade.

    Why it matters: Defines an actionable IGF2BP1/MYCN-PAICS-CHK1 axis linking 17q-gain and MYCN to a purine-metabolism vulnerability and immunotherapy response.

  3. 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. Nature83

    A preinvasive regulatory T cell axis for lung cancer interception.

    BATF-expressing effector regulatory CD4+ T cells (eTreg cells) accumulate in high-grade premalignant airway lesions, are clonally related to circulating eTreg cells, and rise in peripheral blood as lesions progress, allowing lung tumorigenesis to be tracked by blood analysis. In mice, carcinogen-driven tumorigenesis triggered the same preinvasive eTreg axis, and PI3Kδ inhibition reduced circulating and pulmonary Treg cells, increased cDC1s, and reduced lung tumour incidence and size. The work provides a theranostic framework for intercepting lung cancer before invasion.

    Why it matters: It identifies a blood-trackable eTreg cell circuit and a druggable interception strategy for preinvasive lung cancer.

Oct 7Wed
  1. nature.com79

    A preinvasive regulatory T cell axis for lung cancer interception

    An effector regulatory T cell circuit can be monitored in blood samples to track the development of lung cancer. Blocking this immune network in the preinvasive setting intercepts tumorigenesis, reducing both tumour incidence and size. The work identifies a blood-accessible immune axis that could enable tracking and early intervention before invasive disease.

    Why it matters: It links a blood-monitorable regulatory T cell circuit to preinvasive interception of lung tumorigenesis.

  2. 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.

  3. Cancer Cell69

    Chromatin accessibility trajectories reveal pre-cancerous epigenetic priming and an acid-driven immunotherapy-resistant gastric cancer subtype.

    A chromatin accessibility atlas of 650 multistage samples from 439 patients traces epigenetic switches across stepwise gastric tumorigenesis, showing that intestinal metaplasia carries a cancer-resembling priming state that licenses tumor initiation. Advanced tumors split into three epigenomic subtypes: proliferative and mesenchymal-inflammatory subtypes respond to neoadjuvant immunotherapy, while the pseudo-gastric subtype is intrinsically drug resistant. FOSL2-driven up-regulation of H+/K+ ATPase transporters sculpts an acidic milieu suppressing CD8+ T cells, and FOSL2 depletion or the acid blocker vonoprazan sensitizes immunotherapy.

    Why it matters: It defines an acid-driven immunotherapy-resistant gastric cancer subtype and a clinically available drug, vonoprazan, that reverses it.

  4. 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.org58

    Genetic dissection of DNA damage response pathways reveals divergent modulation of PD-1 blockade response in colorectal cancer

    A systematic in vivo screen of altered DNA damage response genes in a genome-edited murine model of MSS colorectal cancer shows that DDR defects have pathway-specific effects on PD-1 blockade response. Loss of Brca1, Brca2, Atm and Fanca enhanced anti-PD-1 response, while Atr and Msh6 deficiency predicted poor benefit, and BRCA1 alterations tracked with improved survival in patients from the MSK-IMPACT cohort. Pre-treatment with pharmacologic ATM inhibition enhanced the antitumor activity of PD-1 blockade in MSS colorectal cancer.

  2. Nat Med67

    Five-year survival with neoadjuvant therapy in melanoma: updated pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC).

    In 1,038 patients with resectable stage IIIB-D melanoma treated across 26 sites, neoadjuvant immune checkpoint inhibitors yielded 5-year recurrence-free survival of 61.0% with PD-1 alone and 73.9% with PD-1 plus another immuno-oncology agent, versus 37.4% with BRAF/MEK inhibitors. Patients achieving a major pathological response had 5-year overall survival of 98.8% and 97.9%, respectively, and gained no benefit from adjuvant ICI continuation. The results define long-term outcomes by regimen and response status.

    Why it matters: It quantifies 5-year survival by neoadjuvant regimen and shows adjuvant ICI adds nothing after major pathological response.

Oct 5Mon
  1. Sci Adv68

    Once yearly cell-based therapy for sustained and dose-tunable delivery of monoclonal antibodies.

    An encapsulated cell-based "biologics factory" using an immunomodulatory alginate formulation sustained stable serum titers of the HIV-neutralizing mAb 3BNC117 for 1 year in immunocompetent mice, supported by an anti-inflammatory, proresolving immune niche that attenuates fibrosis. The platform produced 13 diverse mAbs from an allogeneic cell chassis, and in a nonhuman primate subcutaneous implant maintained stable ipilimumab titers for more than 6 months with no detectable toxicity, antidrug antibodies, or adverse events across a three-dose escalation. A retrievable macrodevice allows on-demand termination and dose-proportional tuning, pointing toward replacing frequent injections with single-administration therapy.

    Why it matters: It shows a single implant can deliver monoclonal antibodies for months to a year, replacing repeated injections.

  2. Mol Cell65

    ZNFX1, an immunoregulatory RNA helicase and E3 ubiquitin ligase, assembles into pleiomorphic polymers.

    Cryo-EM structures of RNA-bound and RNA-free ZNFX1 reveal how a regulatory insertion auto-inhibits the helicase-associated ATPase by occluding the RNA-binding groove. ZNFX1 acts as a bi-catalytic E3 ubiquitin ligase through an RNF213-like RZ finger and a newly identified Miz-like domain, with ubiquitin chains enhancing E3 activity. Patient mutations show the helicase/ATPase, E3 ligase, and connecting zinc-finger stalk are all required for function, and polymer assembly drives trans-auto-ubiquitylation controlling ZNFX1 stability.

    Why it matters: Defines the structural mechanism linking an innate-immunity RNA helicase to ubiquitin signaling and patient mutations.

Oct 3Sat
  1. Cancer Cell73

    Chemotherapy enhances cancer vaccine efficacy and expands stem-like TCF1+CD8+ T cells.

    Carboplatin plus paclitaxel (CarboTaxol) and cyclophosphamide act as immunological adjuvants that improve the efficacy of heterologous prime-boost viral vector vaccines and enhance antigen-specific CD8+ T cell responses, independently of tumor presence. CarboTaxol drives early, antigen-independent expansion of stem-like TCF1+CD8+ T cells, seen also in patients with different cancer types, and disrupting TCF1 abolishes this adjuvant effect. Adding PD-1 blockade further improves tumor control and survival, supporting clinical testing of the triple combination.

    Why it matters: It gives a mechanism, TCF1+CD8+ T cells, for combining chemotherapy with cancer vaccines and PD-1 blockade.

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. Nature62

    Membranolytic peptide programs immunogenic cell death for cancer therapy.

    A synthetic acid-responsive membranolytic peptide, aMPC16-CA50, induces a distinct immunogenic membranolytic cell death in tumour cells, marked by time-lagged rupture from lysosomal to plasma membranes. The peptide activated an inflammatory transcriptional program in tumour cells, boosting class I MHC antigen presentation on dendritic cells and T cell activation, and strengthened the efficacy of immune checkpoint blockade therapy in mice, where systemic administration was well tolerated. It works by hierarchically responding to the falling pH of the tumour extracellular environment and lysosomes, spatiotemporally controlling membrane rupture.

  3. Nature66

    Functional role of skull lymphoid structures in CNS immunosurveillance.

    Lymphoid structures with germinal-centre-like formations exist in skull bone marrow, harbouring follicular-helper-like T cells that promote B cell activation and humoral immunity through CD40L, IL-21 and IFNγ signalling. These adaptive immune cells surveil CNS-derived antigens and contribute to anti-tumour immune responses in mouse brain cancer models, identifying skull bone marrow as a site of CNS immunosurveillance.

  4. biorxiv.org50

    Epithelial to mesenchymal transition and M2 macrophages drive aggressiveness in murine and human sarcomatoid urothelial carcinoma.

    A new murine model of sarcomatoid urothelial carcinoma, BBN966, closely mirrors the human disease: it lacks basal and luminal gene expression, shows the highest epithelial to mesenchymal transition upregulation, and has a higher proportion of M2 macrophage gene expression. In the largest PD-L1 IHC cohort to date, 20 of 38 (52.6%) human SUC had CPS > 50, and anti-PD1 significantly inhibited BBN966 tumor growth, supporting the model for testing new therapies.

  5. doi.org61

    PAK4 exacerbates melanoma immunosuppression by promoting exosome release

    PAK4 drives melanoma immune evasion by boosting exosome release through two mechanisms: phosphorylation of Annexin-A2 at Ser26, which promotes S100A10-ANXA2 heterotetramer formation and multivesicular body docking, and stabilization of synaptotagmin-1 by blocking Trim21-mediated degradation, enabling SNARE complex assembly. PAK4-driven exosomes enriched in PD-L1 reduce CD8+ T cell numbers and impair their function in mouse models, and pharmacological PAK4 inhibition in patient-derived xenografts attenuates tumor progression and lowers circulating exosomal PD-L1. The work supports combining PAK4 inhibitors with immune checkpoint blockade to overcome resistance.

    Why it matters: It defines a mechanism linking PAK4 to PD-L1 exosome release and supports combining PAK4 inhibitors with checkpoint blockade.

  6. nature.com56

    Five-year survival with neoadjuvant therapy in melanoma: updated pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC)

    Neoadjuvant immune checkpoint inhibitors, alone or in combination, outperformed neoadjuvant BRAF/MEK inhibitors for long-term survival in a pooled analysis of 1,038 melanoma patients with 3-year and 5-year data from the International Neoadjuvant Melanoma Consortium. Patients achieving major pathological responses had better long-term survival across treatment types. The results position pathological response as a key indicator of durable benefit from neoadjuvant therapy.

    Why it matters: Five-year pooled survival data across neoadjuvant regimens guide regimen choice for resectable melanoma.

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.

  3. nature.com64

    Transcription pause and elongation regulators mediate somatic hypermutation

    Somatic hypermutation depends on recruitment of activation-induced deaminase to chromatin and on a stalled polymerase II substrate; the molecular factors and mechanisms mediating both have now been identified. The work names the transcription pause and elongation regulators involved, filling a mechanistic gap in how mutation targets are generated during antibody diversification.

    Why it matters: Identifies the transcription regulators that create the substrate for activation-induced deaminase in somatic hypermutation.

  4. nature.com62

    Type 2 immune history trains lung macrophages for viral disease tolerance

    Type 2 inflammation trains nerve- and airway-associated macrophages to confer disease tolerance against lethal influenza. The trained macrophages limit immunopathology and promote tissue repair without enhancing viral clearance, indicating prior type 2 immune history protects through tolerance of infection rather than control of the virus itself.

    Why it matters: It separates disease tolerance from viral clearance as a mechanism for surviving influenza.

  5. nature.com69

    Sugar-rich foods exacerbate antibiotic-induced microbiome disruption

    In patients undergoing allogeneic haematopoietic cell transplantation, intake of sweets during antibiotic exposure predicted lower faecal microbiome α-diversity and increased Enterococcus abundance. The finding, from 9,419 meal samples and 1,009 stool samples across 173 patients, was validated in mice, where dietary sugar supplementation exacerbated and prolonged antibiotic-induced Enterococcus blooms. Short-term sugar avoidance emerges as a testable strategy during antibiotic treatment.

    Why it matters: It identifies a modifiable dietary factor that worsens antibiotic-driven Enterococcus expansion, actionable in hospitalized patients.

Sep 30Wed
  1. medrxiv.org72

    CD3-engaging bispecific antibodies convert human regulatory T cells into cytotoxic effectors

    CD3-engaging bispecific T cell engagers convert human FOXP3+ regulatory T cells into an AP-1-imprinted hybrid cytotoxic state that contributes to tumor clearance. In newly diagnosed multiple myeloma patients treated with BTCE-based induction in the phase 2 GMMG-HD10/DSMM-XX/MajesTEC-5 trial, single-cell sequencing showed Tregs expressing GZMA, GNLY and NKG7, and in vitro BTCE-exposed Tregs killed tumor cells in a target- and dose-dependent manner. IMiDs amplified and reshaped this cytotoxic program, supporting BTCE-IMiD combination regimens.

    Why it matters: Reframes Tregs as active cytotoxic effectors of bispecific antibody therapy and gives a mechanistic basis for BTCE-IMiD combinations.

  2. biorxiv.org66

    Tissue resident CD4+ memory T-cells mark response to immune checkpoint inhibition in high-grade glioma

    Tissue-resident CD4+ memory T cells mark which high-grade gliomas respond to combined PD-1 and CTLA-4 inhibition. In a syngeneic hypermutated glioma model, response involved clonal expansion of tumor-reactive cytotoxic T cells and infiltration of CXCR6+ CD4+ Trm cells, with CD4 stem-like memory cells showing interferon responses rather than exhaustion. In IDH1 wildtype glioblastoma patients treated with neoadjuvant pembrolizumab, CD4+ Trm association with prolonged overall survival was confirmed.

    Why it matters: Identifies a T-cell subset that predicts checkpoint inhibitor response and survival in glioblastoma.

Sep 28Mon
  1. biorxiv.org67

    Disruption of the ARID1A-containing SWI/SNF complex reprograms tumor-associated macrophages and enhances immunotherapy response

    Disrupting the SWI/SNF chromatin remodeling complex in tumor-associated macrophages reprograms them and improves checkpoint blockade immunotherapy. Pharmacologic inhibition of SWI/SNF ATPase activity slowed tumor growth, and deleting the SWI/SNF subunit Arid1a in myeloid cells was sufficient to suppress tumor progression and enhance checkpoint blockade response. The reprogramming involved reduced enhancer accessibility at poor-prognosis genes such as Spp1, increased accessibility at interferon-stimulated gene promoters, elevated CD86, and required CD86 costimulation and CD8+ T cells.

    Why it matters: It identifies a druggable epigenetic target in macrophages that improves checkpoint blockade response.

  2. biorxiv.org54

    Integrated immunopeptidomics and transcriptomics reveal a cancer-restricted non-canonical HLA class I ligandome in medulloblastoma

    Non-canonical HLA class I peptides could widen the target pool for T-cell immunotherapy in medulloblastoma, a tumor with low mutational burden. Integrated immunopeptidomics and transcriptomics across 21 samples covering the four molecular subgroups identified 2,298 non-canonical HLA-I peptides, 598 of them cancer-restricted, derived mainly from retained introns, out-of-frame open reading frames, and long non-coding RNAs. More than 70% were predicted to bind a patient-matched HLA allotype and about 87% to be immunogenic.

    Why it matters: It expands the antigen repertoire available for T-cell therapy in a low-mutational-burden childhood brain tumor.

  3. biorxiv.org62

    BLTP3A dysfunction unleashes lysosomal stress-induced antitumor immunity through STING

    A common germline missense variant in BLTP3A, M1098T, impairs lysosomal stress resolution in high-grade serous ovarian cancer, prolonging STING activity and tumor-derived IFN-λ. Patients carrying M1098T had longer overall survival and tumors enriched for cytotoxic T cell-myeloid neighborhoods. In syngeneic tumors, Bltp3a loss or the orthologous variant delayed progression and generated Cxcl9+ antigen-presenting macrophage niches, with tumor-cell STING and IFN-λ required for immune remodeling and tumor control.

    Why it matters: Links a germline variant to antitumor immunity and survival via lysosomal stress and STING.

  4. biorxiv.org61

    A druggable chromatin vulnerability in suppressive neutrophils restores antitumor immunity

    Suppressive neutrophils (PMN-MDSCs) depend on mSWI/SNF chromatin remodeling to maintain their identity, and two orally bioavailable mSWI/SNF ATPase antagonists, a degrader and a catalytic inhibitor, produced immune-dependent tumor control in syngeneic models, including tumors resistant to PD-1 blockade. Treatment depleted intratumoral PMN-MDSCs, restored functional CD8+ T cells, enhanced checkpoint therapy without overt toxicity, and blocked PMN-MDSC expansion in mouse and human cells. Mechanistically, antagonism collapsed chromatin accessibility and PU.1/C/EBPβ occupancy at regulatory elements sustaining PMN-MDSC identity.

    Why it matters: It identifies a druggable chromatin dependency of PMN-MDSCs and shows it can restore antitumor immunity and checkpoint response.

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