Proteomic and phosphoproteomic analyses of lysosomes uncovered a TBK1/ULK1 signalling axis that activates TFEB in response to lysosomal stress, independent of nutrient-sensing by mTORC1. This regulatory arm mediates lysosomal adaptation to stress, and its deregulation was linked to tumorigenesis in follicular lymphoma. The work adds a nutrient-independent branch to the mTORC1 signalling framework at the lysosome.
Osteoclast-derived angiopoietin-2 in the dura mater impairs lymphatic vessel function and weakens anti-tumour immunity against dural metastases. The work identifies osteoclasts as interceptors of meningeal lymphatic paths and points to selective osteoclast targeting as a way to restore meningeal lymphatic function and anti-tumour immunity. No numerical results are given.
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.
Desharnais et al. show in Nature that across diverse mouse models, anti-PD-1 sensitivity tracks more closely with the diet-microbiome-metabolite ecosystem than with obesity-associated metabolic dysfunction. The findings point to body mass index as an incomplete proxy for host biology and suggest strategies to improve anti-PD-1 efficacy without inducing obesity.
Jesus G. Berdeja of Tennessee Oncology and Ajai Chari of UCSF discussed sequencing of T-cell redirecting therapies, including ADCs, bispecific antibodies and CAR-T, in relapsed/refractory multiple myeloma in a Decera Clinical Education session recorded before the FDA approved iberdomide plus daratumumab and dexamethasone. They said no randomized data define the optimal order, so decisions rely on prior treatment history, depth of response, comorbidities and drug access, with early use improving PFS while OS benefit awaits longer follow-up. CAR-T options such as idecabtagene vicleucel and ciltacabtagene autoleucel show deep responses but face manufacturing time and cost limits, whereas off-the-shelf bispecifics like teclistamab, talquetamab and elranatamab can be given immediately but carry CRS, ICANS and infection risks.
Splicing factor mutations in myeloid neoplasms poison entire functional protein complexes, not just individual transcripts. Single-cell transcriptomics (10X-ONT, n = 21) and immunophenotype-resolved pauciproteomics (n = 78) across 62 patients and 20 healthy donors show that mutation-specific RNA mis-splicing decouples protein from transcript dynamics during hematopoietic differentiation, effects invisible to transcriptomics alone and validated in iPSC differentiation models.
Why it matters: Protein-level consequences of splicing factor mutations are invisible to transcriptomics, changing how these oncogenic events should be studied.
A TIGEM team publishing in Nature found that TBK1 and ULK1 are activated under lysosomal stress, modify FNIP1, and use TAX1BP1 to drive TFEB into the nucleus to turn on cell recycling genes. Acting upstream of TFEB, the pathway sidesteps the difficulty of drugging transcription factors and may apply to TFEB-linked diseases such as lysosomal storage disorders, neurodegenerative diseases, and follicular lymphoma. DOI: 10.1038/s41586-026-11093-3.
An MIT team publishing in Nature Genetics reports that some lung adenocarcinomas can evade KRAS-G12C inhibitors through adenosquamous transformation, losing dependence on the KRAS signaling pathway. The researchers reproduced this transformation in a mouse lung adenocarcinoma model by knocking out Nkx2-1 and activating the transcription factors DeltaNp63 and SOX2. The two FDA-approved KRAS-G12C inhibitors are effective in about 35% of patients, and most responding cases eventually develop resistance.
Why it matters: The paper reproduces a less-discussed KRAS inhibitor resistance route, adenosquamous transformation, in a mouse model and identifies key transcription factors, giving readers a new comparison for similar resistance mechanisms.
Intravenous zabilugene almadenorepvec (VCN-01), a hyaluronidase-expressing oncolytic adenovirus, plus gemcitabine and nab-paclitaxel prolonged overall survival over chemotherapy alone in the randomized phase 2b VIRAGE trial in treatment-naive metastatic pancreatic cancer. The finding supports adding an oncolytic virus to standard first-line chemotherapy in this setting.
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.
Common-Sense Oncology and the European Organisation for Research and Treatment of Cancer issued recommendations on reporting health-related quality of life in randomised clinical trials of adjuvant systemic therapy after locoregional cancer treatment. They argue that because many adjuvant therapies yield small gains in relapse-free or overall survival, side-effects and their effect on patient functioning and HRQOL must be reported to inform clinical decision making.
High-risk neuroblastoma shows robust disruption of coordinated circadian gene network organisation, and the alteration is distributed across the network rather than driven by single clock genes. Delta-CCD, a measure of network dysregulation, was highest in high-risk tumours in two cohorts (SEQC, n=498; Kocak, n=649) across canonical, adrenal-tissue matched and developmental references. MYCN-amplified and stage 4 tumours showed a more reference-dependent pattern, strongest in the adrenal context.
Why it matters: It reframes circadian disruption in high-risk neuroblastoma as a network-level alteration, not a single-gene effect, across two cohorts.
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.
The TWISTAR platform deorphanizes single-cell-derived TCRs against tumor transcriptomes and directly validates TCR engagement, so it recovers only functionally immunogenic antigens. Applied to melanoma, breast, and hepatocellular carcinoma patients responding to immune checkpoint blockade, it shows tumor-reactive TCRs recognize many targets beyond neoantigens, including peptides from unannotated coding sequences and novel transcripts. Many antigens are shared across patients and cancer types, with multiple T cell clones converging on a few immune dominant epitopes, supporting pan-cancer vaccine development.
A noncanonical nuclear role of FAH, an enzyme in the tyrosine catabolism pathway, drives resistance to CDK4/6 inhibitors in HR+ breast cancer. In patient-derived models and tumors, FAH translocated to the nucleus upon CDK4/6 inhibition, bound CDK9, and promoted resistance; nuclear FAH was enriched in tumors from relapsed patients. CDK9 inhibition reversed FAH-mediated resistance, establishing nuclear FAH as a resistance biomarker and CDK9 as a therapeutic vulnerability.
Merck and Daiichi Sankyo have voluntarily withdrawn their accelerated approval application for the antibody-drug conjugate ifinatamab deruxtecan (I-DXd) in extensive-stage small cell lung cancer after platinum-based chemotherapy, after the FDA said the data did not satisfy requirements for the proposed indication. The application rested on a 48.2% confirmed objective response rate from the Phase 2 IDeate-Lung01 study. A Phase 3 trial in ES-SCLC with enrollment nearing completion continues and could support a future filing.
Merck is licensing a KRAS G12D inhibitor from entrepreneur and synthetic chemist Tao Hu for $400 million upfront. Hu previously sold a different KRAS G12D inhibitor to AstraZeneca in 2023. Terms beyond the upfront payment and next steps were not disclosed.
Tumor cell-intrinsic oxidative and proteotoxic stress pathways modulate response to CAR T cell therapy in pancreatic ductal adenocarcinoma. Using in vivo CRISPR screens, single-cell genomics and immunocompetent orthotopic PDAC models, disruption of stress regulatory genes, especially Keap1 and Slc33a1, sensitized tumors to CAR T cell killing in vivo. Clinically observed Keap1 or Nfe2l2 mutations, and Keap1 loss activating the Nrf2 pathway, likewise increased susceptibility, suggesting tumor genotype could stratify patients for CAR T cell therapy.
Roche has stopped developing emugrobart, an anti-myostatin antibody intended to spare lean mass during weight loss, and rights revert to Chugai, which plans to resume development for spinal muscular atrophy and advance it into Phase 3. Roche had been testing the drug in the Phase 2 GYMINDA trial in combination with tirzepatide. The exit removes Roche's myostatin-targeting approach from the obesity field, leaving enicepatide and petrelintide as its main obesity assets.
Why it matters: A major pharma abandoning a muscle-preserving obesity mechanism reshapes the competitive landscape and returns the asset to Chugai for Phase 3 in SMA.
AstraZeneca is investing $2 billion in Summit Therapeutics through a direct equity purchase of about 109,000 preferred shares, giving it roughly 12% of Summit's common shares at $18.36 per share, a 10% premium. The deal, expected to close within a week pending regulatory clearances, lifts Summit's cash to an estimated $2.5 billion and leaves it holding full rights to ivonescimab, the PD-1/VEGF bispecific, in its territories. The partners will also start trials pairing AstraZeneca's anti-CLDN18.2 ADC sonesitatug vedotin with ivonescimab in gastrointestinal cancers, while the FDA decides Summit's BLA for the NSCLC drug by Nov. 14.
