A terminally differentiated protumor neutrophil subset, TAN1, marked by a glycolysis signature and senescent phenotype, is enriched in colorectal cancer liver metastasis and linked to poor prognosis. Single-cell and spatial-enhanced-resolution-omics sequencing show TAN1 arises from other tumor-associated neutrophil subsets via BHLHE40 upregulation driven by glucose deprivation, and promotes angiogenesis through VEGFA while recruiting immunosuppressive macrophages via CCL3L1-CCR1 signaling. Neutrophil-specific Bhlhe40 knockout in mice boosted antitumor immunity and suppressed tumor growth, pointing to a neutrophil-specific therapeutic target.
Quantitative temporal profiling of the global, phosphorylation, and surface proteome in PDAC shows that KRAS inhibition upregulates the cell surface protein ALPP through compensatory JAK2/STAT3 signaling. The authors developed a clinical-grade ALPP/ALPPL2-targeting antibody drug conjugate with site-specific MMAE conjugation, which showed single-agent efficacy in PDAC models and enhanced internalization and anti-tumor efficacy combined with KRAS inhibitors, pointing to a combination strategy to forestall KRASi resistance.
PAK4 phosphorylates ANXA2 at Ser26, promoting its nuclear-to-cytoplasmic translocation and formation of S100A10-ANXA2 heterotetramers, while stabilizing synaptotagmin-1 by suppressing Trim21-mediated ubiquitin degradation. Through these actions it drives exosome release from multivesicular bodies and exacerbates melanoma immunosuppression.
Why it matters: The paper defines a dual PAK4 mechanism of exosome-driven melanoma immunosuppression, supporting combination of PAK4 inhibitors with immune checkpoint blockade.
Proceedings of the National Academy of Sciences of the United States of AmericaPickScore6161
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.
MRI surveillance alone beat prophylactic cranial irradiation plus MRI on cognitive failure-free survival in the phase 3 SWOG S1827 MAVERICK trial. In 304 patients with limited and extensive-stage small-cell lung cancer who had completed initial therapy, MRI-only monitoring improved the primary endpoint (HR 0·60, 90% CI 0·46–0·78; p=0·001) at a median follow-up of 22 months. The result challenges routine prophylactic cranial irradiation, long tied to better survival but more neurological toxicity.
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.
Foghorn Therapeutics and Eli Lilly ended their oncology collaboration after Phase 1 data on cancer candidate FHD-909 (LY4050784) showed insufficient efficacy, halting its move into clinical development expansion and a SMARCA2 degrader program. Foghorn is cutting about 40% of its workforce, leaving roughly 65 full-time employees, and will refocus on its proprietary programs including EP300 and CBP degraders. The 2021 deal had brought $300 million upfront plus an $80 million equity investment from Lilly's Loxo Oncology, and the changes should extend Foghorn's cash runway into the second half of 2029.
Why it matters: A terminated big-pharma oncology alliance triggers pipeline reprioritization, layoffs and a readout on the SMARCA2 synthetic lethality hypothesis.
HTLV-1 antisense protein HBZ stabilizes a Fra-2/p65 complex that rewires NF-κB transcription toward IL-1β in tax-negative adult T-cell leukemia/lymphoma, driving inflammatory chemoresistance. IL-1β was elevated in ATL patient sera and cells independently of proviral load, and blocking IL-1 signaling with anakinra or anti-IL-1β antibodies restored doxorubicin sensitivity in primary ATL cells. The work identifies the Fra-2-NF-κB-IL-1β axis as a targetable driver of chemoresistance.
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.
AstraZeneca will invest $2 billion in Summit Therapeutics by subscribing to convertible preferred shares, giving it about 12% of the company after conversion. Alongside the equity stake, announced September 28, the two firms signed a binding clinical collaboration combining Sone-Ve with Ivonescimab in GI tumors, plus a non-binding MOU to explore pairing Ivonescimab with more of AstraZeneca's ADC portfolio.
China's NMPA has approved Bristol Myers Squibb's iberdomide capsules (brand name Zanfu) via priority review on September 30, 2026, in combination with daratumumab and dexamethasone for adults with multiple myeloma who received at least one prior line including a proteasome inhibitor and an immunomodulatory drug. Iberdomide is the first approved Cereblon E3 ubiquitin ligase modulator (CELMoD) and BMS's first marketed product from its targeted protein degradation work.
The 2026 edition of the CSCO primary liver cancer guideline has raised yttrium-90 microsphere SIRT (selective internal radiation therapy) to a Grade I, Category 1A recommendation. At the CSCO annual meeting's nuclear medicine session, Professors Yang Aimin of the First Affiliated Hospital of Xi'an Jiaotong University and Jia Weidong of the First Affiliated Hospital of USTC presented a new Chinese expert consensus on whole-process nuclear medicine management of Y-90 SIRT for liver malignancies. Jia Weidong discussed SIRT as a new option in conversion therapy for liver cancer.
An all-oral regimen of giredestrant plus everolimus significantly prolonged progression-free survival over standard endocrine therapy plus everolimus in ER-positive, HER2-negative advanced breast cancer after a CDK4/6 inhibitor. Among 207 patients with ESR1-mutated tumors, median progression-free survival was 10.0 versus 5.5 months (hazard ratio 0.38); in the overall population of 373 patients, it was 8.8 versus 5.5 months (hazard ratio 0.56). Adverse-event rates were similar between groups.
Why it matters: Phase 3 data show an all-oral targeted combination doubles progression-free survival after CDK4/6 inhibition, especially in ESR1-mutated tumors.
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.
RO7589831 (VVD-133214), a first-in-class covalent inhibitor of Werner syndrome helicase, showed manageable safety and early antitumor activity in 88 patients with MSI and/or mismatch repair-deficient advanced solid tumors in part 1 of a phase 1 trial. TEAEs were mostly grade 1-2, with no grade 5 events and discontinuation in 3.4% (3/88). In 66 MSI efficacy-evaluable patients, disease control rate was 74.2%, objective response rate 10.6% (7 partial responses), median PFS 6.7 months and median OS 17.6 months; 150 mg and 600 mg BID were selected as recommended phase 2 doses.
Loss of the tumor suppressor p53 generates a signaling gradient that drives epithelial clonal expansion. The paper appears in Science, Volume 394, Issue 6819, October 2026, DOI: 10.1126/science.aed3065.
Why it matters: The headline proposes that p53 loss generates a signaling gradient driving epithelial clonal expansion, background for how p53 inactivation promotes tumor initiation.
China's NMPA has approved Merck's subcutaneous formulation of the PD-1 inhibitor pembrolizumab, covering 19 solid tumour indications, making it the first and currently only subcutaneous PD-1 inhibitor approved in China. The approval, announced on 29 September 2026, is based on data from study MK-3475A-D77. The approval covers the same indication set as the existing intravenous formulation.
The FDA has approved a new drug for pancreatic cancer that reportedly extends survival in patients. The approval was reported by Scientific American on August 26 and relayed by Chinese industry media on August 29. No drug name, trial details or dosing information were given in the report.
Merck has licensed SPR2015, a preclinical molecular-glue KRAS G12D (ON) inhibitor, from Shanghai-based Sipurui, gaining worldwide rights to the candidate. Sipurui receives $400 million upfront, about 2.684 billion RMB, plus potential milestone payments tied to development and commercialization across multiple indications. KRAS was long considered undruggable because its protein lacks a clear binding pocket.
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.
