Zhou T, Yan J, Mao G
… +26 more, Zhang Y, Shi S, Hu T, Xu J, Zhang Y, Ji Z, Fang Q, Zhang Z, Li Z, Liu Z, Wang Y, Wang H, Zhao T, Gao S, Wang X, Yang C, Huang C, Liu J, Chang A, Yang S, Yu J, Feng Y, Liu R, Xie Y, Wang B, Hao J
Cancer Discov
· 2026 Mar · PMID 41891402
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Lymph node metastasis (LNM) in early-stage PDAC predicts systemic dissemination and poor survival, yet its underlying mechanisms remain elusive. Here, we demonstrated that senescent cancer-associated fibroblasts (senCAFs...Lymph node metastasis (LNM) in early-stage PDAC predicts systemic dissemination and poor survival, yet its underlying mechanisms remain elusive. Here, we demonstrated that senescent cancer-associated fibroblasts (senCAFs) drive lymphatic remodeling and LNM in early-stage PDAC. Mechanistically, senCAFs increased glucose metabolism and lactate production, which activated lactylation-mediated serine metabolism to protect lymphatic endothelial cells from oxidative stress. Moreover, we discovered CCR4+ Tregs from the draining lymph nodes accumulated around lymphatic vessels, which established an immunosuppressive peri-lymphatic niche. High throughput drug screening determined selective clearance of senCAFs via chidamide, attenuated tumor progression and improved chemo-immunotherapeutic efficacy. We subsequently initiated a clinical trial (chidamide and nab-paclitaxel/gemcitabine plus anti-PD-1/CTLA-4) in metastatic PDAC patients and reported its preliminary promising results. Collectively, these findings reveal a closed link between cellular senescence and PDAC metastasis, offering the potential senolytic means to improve chemo-immunotherapy efficacy.
Uzunparmak B, Su F, Johnson A
… +22 more, Shaw KRM, Kong EK, Korkut A, Braganca Xavier C, Yuan Y, Fowler NH, Paradiso F, Kontselidze L, Butusova A, Bagaev A, Dumbrava EE, Rodon J, Hong DS, Yap TA, Fu S, Naing A, Piha-Paul SA, Ferrarotto R, Bryan J, Kulkarni S, Patel KP, Meric-Bernstam F
Cancer Discov
· 2026 Mar · PMID 41885383
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The added value of comprehensive genomic and transcriptomic profiling (CGTP) with whole exome sequencing (WES) and whole transcriptome sequencing (WTS) as compared to conventional targeted panel-based sequencing is not w...The added value of comprehensive genomic and transcriptomic profiling (CGTP) with whole exome sequencing (WES) and whole transcriptome sequencing (WTS) as compared to conventional targeted panel-based sequencing is not well-characterized for patients with cancer. We thus sought to determine the potential clinical utility of CGTP in a prospective clinical study in patients with advanced or metastatic solid tumors. We performed WES and WTS for patients who had prior targeted panel sequencing and had no DNA alterations with approved biomarker-matched therapies. We analyzed CGTP data of 99 patients with advanced cancers across 19 solid tumor types and assessed presence of actionable DNA alterations and RNA expressions linked to approved or investigational agents. CGTP identified actionable genomic and transcriptomic alterations in 69.7% and 100% of cases, respectively. In this pilot study where CGTP was incorporated into routine care, 19.2% of patients received biomarker-matched therapy.
Clusmann J, Koop PH, Zhang DY
… +13 more, van Haag F, El Nahhas OSM, Seibel T, Žigutytė L, Kaewdech A, Calderaro J, Tacke F, Luedde T, Truhn D, Bruns T, Schneider KM, Kather JN, Schneider CV
Cancer Discov
· 2026 Jul · PMID 41881847
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UNLABELLED: Hepatocellular carcinoma (HCC) is a highly fatal tumor, for which risk stratification is crucial yet remains challenging. In this study, we develop an interpretable machine learning (ML) framework for HCC ris...UNLABELLED: Hepatocellular carcinoma (HCC) is a highly fatal tumor, for which risk stratification is crucial yet remains challenging. In this study, we develop an interpretable machine learning (ML) framework for HCC risk stratification based on routinely collected clinical data. We utilize prospectively collected multimodal data from more than 900,000 individuals and 983 cases of HCC across two population-scale cohorts: the UK Biobank study (development) and the All of Us Research Program (external testing). We assess individual and cumulative contributions of data modalities, including demographics, lifestyle, health records, blood, genomics, and metabolomics. Our final random forest-based models significantly outperform all publicly available state-of-the-art risk scores on both internal and external test sets. We demonstrate robustness across ethnic subgroups, provide comprehensive interpretability, and release all code, model weights, and a web calculator for external validation and agentic integration. Our study presents PRE-Screen-HCC, a robust and interpretable ML framework for HCC risk stratification and early detection. SIGNIFICANCE: Using data from population-scale cohorts, we develop and externally validate an ML framework for HCC risk stratification. Models trained on routine clinical data outperform published scores, perform on par with metabolomics and genomics, generalize across subgroups, and remain interpretable. See related commentary by Foda, p. 1252.
Cancer Discov
· 2026 May · PMID 41881687
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A deep-learning model applied to chest CT scans reveals that variation in thymus health tracks with both cancer susceptibility and clinical response after treatment with checkpoint inhibitors. The findings point to routi...A deep-learning model applied to chest CT scans reveals that variation in thymus health tracks with both cancer susceptibility and clinical response after treatment with checkpoint inhibitors. The findings point to routine imaging data as a scalable approach to risk assessment and therapy selection, and highlight the underappreciated role of thymic function in shaping cancer outcomes.
Zheng J, Zhao S, Zhan J
… +21 more, Zhuang W, Chen M, Jiang W, Huang Y, He J, Hu L, Pang L, Hao F, Xue J, Shi M, Li A, Wu J, Hong S, Zhao Y, Ye F, Huang Y, Zhao H, Yang Y, Fang W, Zhang L, Li J
Cancer Discov
· 2026 Mar · PMID 41874451
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While epidermal growth factor receptor (EGFR) fusions in non-small cell lung cancer (NSCLC) typically show sensitivity to tyrosine kinase inhibitors (TKIs), we identified an EGFR-SHC1 fusion subtype that exhibits intrins...While epidermal growth factor receptor (EGFR) fusions in non-small cell lung cancer (NSCLC) typically show sensitivity to tyrosine kinase inhibitors (TKIs), we identified an EGFR-SHC1 fusion subtype that exhibits intrinsic resistance to EGFR-TKI monotherapy through a dual activation mechanism in the preclinical and clinical setting. EGFR-SHC1 fusion protein comprises of N-terminal EGFR and C-terminal SHC1. We demonstrated that EGFR-SHC1 simultaneously activates the EGFR kinase domain (KD) and SRC-mediated phosphorylation of the SHC1 fusion partner, thereby driving ERK/AKT pathway activation and tumorigenesis independent of KD inhibition. Structural modeling coupled with domain-specific mutagenesis revealed that SHC1 phosphorylation establishes a kinase-independent bypass mechanism. Notably, dual-targeted inhibition using afatinib (EGFR-TKI) in combination with dasatinib (SRC-TKI) induced marked tumor regression in a TKI-refractory NSCLC patient with EGFR-SHC1. This study illustrates a cooperative oncogenesis between kinase and scaffold protein in fusions, providing a clinically actionable strategy for overcoming TKI resistance in patients with these oncogenic fusions.
Yiu SPT, Chang Y, Yeo YY
… +57 more, Qiu H, Wu W, Michel HA, Jin X, Huang R, Kure S, Parmelee L, Luo S, Cramer P, Lee JL, Wang Y, Zhao Z, Yeung J, El Ahmar N, Simsek B, Mohanna R, Van Orden M, Lu WS, Livak KJ, Li S, Gao C, Burgess M, Keane C, Shahryari J, Kingsley LG, Al-Humadi RN, Nasr S, Nkosi D, Sadigh S, Rock P, Frauenfeld L, Kaufmann L, Zhu B, Basak A, Dhanikonda N, Chan CN, Krull J, Cho YW, Chen CY, Brown J, Wang H, Zhao B, Lee JJ, Loo LH, Kim DM, Boussiotis VA, Zhang B, Wei K, Shalek AK, Howitt BE, Signoretti S, Schürch CM, Hodi FS, Burack WR, Rodig SJ, Ma Q, Jiang S
Cancer Discov
· 2026 Mar · PMID 41874448
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Spatial transcriptomics and proteomics have enabled profound insights into tissue organization, yet these technologies remain largely disparate, and emerging same-slide multi-omics approaches are limited in plex, spatial...Spatial transcriptomics and proteomics have enabled profound insights into tissue organization, yet these technologies remain largely disparate, and emerging same-slide multi-omics approaches are limited in plex, spatial resolution, signal retention, and integrative analytics. We introduce IN-situ DEtailed Phenotyping To High-resolution transcriptomics (IN-DEPTH), a streamlined, resource-efficient, commercially compatible workflow using single-cell spatial proteomics-derived imaging to guide transcriptomic capture on the same slide without RNA signal loss. To integrate modalities beyond niche-level mapping, we developed Spectral Graph Cross-Correlation (SGCC), a proteomic-transcriptomic framework resolving spatially coordinated functional state changes across interacting cell populations. Applied to diffuse large B-cell lymphoma (DLBCL), IN-DEPTH and SGCC enabled stepwise discovery from EBV-positive and EBV-negative tumor comparisons to single-cell resolution, revealing coordinated tumor-macrophage-CD4 T-cell remodeling, immunosuppressive C1Q macrophage enrichment, CD4 T-cell dysfunction, and a candidate IL-27-STAT3 signaling axis. Collectively, IN-DEPTH enables scalable spatial multi-omics to uncover clinically relevant microenvironmental mechanisms and towards robust spatial multi-modal AI models.
Cancer Discov
· 2026 May · PMID 41855558
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Cancer Grand Challenges, a US-UK funding initiative, announced the five teams that will receive up to £20 million (about $27 million) for 5 years. The teams are pursuing bold projects in underexplored fields of cancer re...Cancer Grand Challenges, a US-UK funding initiative, announced the five teams that will receive up to £20 million (about $27 million) for 5 years. The teams are pursuing bold projects in underexplored fields of cancer research and will have the flexibility to pursue new directions as their research evolves.
Cancer Discov
· 2026 May · PMID 41817445
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A massive study spanning 185 countries concludes that about four in 10 cancer cases are linked to modifiable risk factors such as smoking, infections, and alcohol consumption. Stratifying by sex, researchers found three...A massive study spanning 185 countries concludes that about four in 10 cancer cases are linked to modifiable risk factors such as smoking, infections, and alcohol consumption. Stratifying by sex, researchers found three in 10 cancer cases in women and one in two in men were due to modifiable risk factors. The findings "reinforce the call for effective cancer prevention," the researchers say.
Cancer Discov
· 2026 May · PMID 41817436
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The NHS-Galleri trial, the first randomized, controlled trial of the multi-cancer early detection test Galleri, found that the test from GRAIL did not meet its primary endpoint, a reduction in late-stage cancers. Researc...The NHS-Galleri trial, the first randomized, controlled trial of the multi-cancer early detection test Galleri, found that the test from GRAIL did not meet its primary endpoint, a reduction in late-stage cancers. Researchers say the result could be a consequence of the trial design, which used a surrogate endpoint rather than cancer-specific mortality, the standard measure.
Cancer Discov
· 2026 May · PMID 41805886
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Two international phase III trials-LITESPARK-022 and LITESPARK-011-demonstrate the potential benefits of the HIF-2α inhibitor belzutifan for patients with clear cell renal cell carcinoma. When combined with the PD-1 inhi...Two international phase III trials-LITESPARK-022 and LITESPARK-011-demonstrate the potential benefits of the HIF-2α inhibitor belzutifan for patients with clear cell renal cell carcinoma. When combined with the PD-1 inhibitor pembrolizumab as an adjuvant treatment, it reduced the risk of disease recurrence by 28% and prolonged disease-free survival over pembrolizumab alone. For patients whose disease returned following immunotherapy, belzutifan and the VEGFR inhibitor lenvatinib bested the VEGFR inhibitor cabozantinib in overall response, progression-free survival, and duration of response.
Cancer Discov
· 2026 May · PMID 41805867
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The Mikaela Naylon Give Kids a Chance Act was signed into law as part of the fiscal year 2026 federal appropriations package. It renews the priority review voucher program for rare pediatric diseases and allows the FDA t...The Mikaela Naylon Give Kids a Chance Act was signed into law as part of the fiscal year 2026 federal appropriations package. It renews the priority review voucher program for rare pediatric diseases and allows the FDA to require combination studies of adult cancer drugs in children, incentivizing research in an area industry is often reluctant to invest in.
Piotrowska Z, Ahn MJ, Voon PJ
… +15 more, Pang YK, How SH, Kim SW, Cortinovis D, de Castro Carpeño J, Tiseo M, Rodríguez Abreu D, Ramalingam SS, Li J, Servidio L, Taylor R, Hartmaier R, Markovets AA, Tang KH, Cho BC
Cancer Discov
· 2026 Jun · PMID 41790042
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UNLABELLED: ELIOS (NCT03239340) prospectively compared tumor biopsies obtained pre-treatment and post-progression to characterize acquired resistance mechanisms to first-line osimertinib in epidermal growth factor recept...UNLABELLED: ELIOS (NCT03239340) prospectively compared tumor biopsies obtained pre-treatment and post-progression to characterize acquired resistance mechanisms to first-line osimertinib in epidermal growth factor receptor (EGFR)-mutant advanced non-small cell lung cancer (NSCLC). Of 154 patients enrolled, 52 patients had next-generation sequencing (NGS) results from paired tissue biopsies. The most common acquired alterations at progression were MET amplification (17%), deletion of CDKN2A/CDKN2B (15%) and MTAP (13%), and EGFR C797S (13%). Proteogenomic analysis (n = 32 at baseline and n = 18 post-progression) showed TROP2 was highly expressed at baseline and post-progression, irrespective of genetic alterations observed. In a separate analysis of patients with matched tissue and plasma samples post-progression (n = 51), 82% had potential resistance alterations by NGS, demonstrating the complementary roles of tissue and plasma NGS. These results highlight the challenges of obtaining tissue biopsies in patients with NSCLC progressing on targeted therapy, the potential for heterogeneous resistance, and the need for broad-acting treatment strategies. SIGNIFICANCE: ELIOS confirmed acquired resistance mechanisms to first-line osimertinib in a prospective, molecular profiling study of paired pre- and post-treatment tissue samples and provided the first proteogenomic characterization before/after osimertinib, identifying novel proteomic markers. ELIOS showed the potential for heterogeneous resistance, highlighting that strategies targeting multiple resistance pathways may be required.
Stahlhut C, Maciag AE, Sullivan KA
… +33 more, Singh K, Gitego N, Zhang Z, Chan AH, Sharma AK, Alexander PA, Shu J, Yang Y, Rigby M, Ma R, Setoodeh S, Smith BP, Pei J, Rabara D, Larsen EK, Turner DM, Zhang C, Feng C, Feng S, Stice JP, Xu R, Lin K, Stephen AG, Lightstone FC, Ji C, Wang K, Simanshu DK, Nissley DV, Wallace E, Wang B, Sinkevicius KW, McCormick F, Beltran PJ
Cancer Discov
· 2026 Apr · PMID 41790032
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UNLABELLED: Although KRASG12C-specific inhibitors have been introduced, no approved targeted therapies exist for other clinically significant KRAS mutants, including KRASG12D and KRASG12V. We discovered BBO-11818, a pote...UNLABELLED: Although KRASG12C-specific inhibitors have been introduced, no approved targeted therapies exist for other clinically significant KRAS mutants, including KRASG12D and KRASG12V. We discovered BBO-11818, a potent, selective, orally bioavailable noncovalent pan-KRAS inhibitor capable of targeting multiple KRAS mutants in both the inactive GDP-bound (OFF) and active GTP-bound (ON) states. BBO-11818 binds in the Switch-II/Helix 3 pocket, inducing conformational changes incompatible with effector binding, and demonstrates high-affinity binding to mutant KRAS with strong selectivity over NRAS and HRAS. BBO-11818 potently inhibited MAPK signaling and cellular viability specifically in KRAS-driven lines and produced tumor regressions in KRAS-mutant xenograft models. Combination studies with anti-PD-1, anti-EGFR antibodies, and a RAS:PI3Kα breaker compound showed enhanced efficacy. BBO-11818 has entered phase I clinical trials for patients with various KRAS mutations in colorectal, pancreatic, and lung cancers (NCT06917079). SIGNIFICANCE: We discovered BBO-11818, a potent and selective noncovalent KRAS inhibitor with activity against multiple KRAS mutants in both the active (ON) and inactive (OFF) states. BBO-11818 addresses the need for KRAS inhibitors targeting clinically relevant mutants such as KRASG12D and KRASG12V, either as monotherapy or in combination.
Deng J, Pal A, Testa S
… +34 more, Xu JW, Tran LM, Graham DS, Hargil A, Subramanian A, Campbell KM, Limsuwannarot S, Chumpitaz Lavalle Á, Chin SC, Kremer S, Tariveranmoshabad M, Ewongwo A, Silvia SKNR, Ogana H, Nemat-Gorgani N, Dubinett SM, Jaycox JR, Felix C, Schaue D, Nelson SD, Levine B, Motamedi K, Ghazikhanian V, Chmielowski B, Reddy V, Singh AS, Trnkova ZJ, Good Z, Quintero M, Crompton JG, Bernthal N, Eilber FC, Moding EJ, Kalbasi A
Cancer Discov
· 2026 Jul · PMID 41784328
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UNLABELLED: Neoadjuvant immune checkpoint blockade (ICB) and radiotherapy (RT) improve disease-free survival in select patients with soft-tissue sarcoma (STS). However, most STS are myeloid-rich and lack preexisting T ce...UNLABELLED: Neoadjuvant immune checkpoint blockade (ICB) and radiotherapy (RT) improve disease-free survival in select patients with soft-tissue sarcoma (STS). However, most STS are myeloid-rich and lack preexisting T cells associated with ICB response. In preclinical models, we observed that intratumoral BO-112 [nanoplexed polyinosinic: polycytidylic acid (poly I:C)] engages myeloid cells that persist after RT, ultimately enhancing T cell-dependent tumor control. We evaluated BO-112 and hypofractionated RT, with or without nivolumab, in 14 patients with high-risk STS in a phase I neoadjuvant trial. Consistent with its immunologic potency, the triple combination induced rare immune-related adverse events (myositis-myocarditis-myasthenia gravis spectrum), mitigated by BO-112 and nivolumab dose adjustment. BO-112 and RT reprogrammed tumor-associated myeloid cells toward antigen-presenting states, promoted clonal replacement by less exhausted T cells, and enhanced malignant cell depletion compared with standard RT. These immunologic changes coincided with encouraging disease control in a small, high-risk cohort, supporting further clinical development. SIGNIFICANCE: Intratumoral BO-112 and hypofractionated RT activate systemic T-cell immunity in mouse models and in a phase I neoadjuvant study of high-risk, resectable sarcoma. Engaging myeloid cells with BO-112 represents a potent strategy with RT to replete T cell-deficient tumors and expand the benefits of neoadjuvant ICB.
Liu XZ, Panina Y, Cai W
… +39 more, Fernández-García J, Peng-Winkler Y, Mao J, Dahlhaus A, Zhou HC, Liu M, Planque M, Ceuppens J, Igelmann S, Spotbeen X, Idkowiak J, Dehairs J, Theile J, Axarlis K, Borremans K, Van Cauwenberge J, Ghanate A, Tarragó-Celada J, Suárez-Bonnet A, Mitter R, Wu V, Inglese P, McKenzie JS, Steven RT, Dexter A, Yan B, Vorng JL, Takáts Z, Bunch J, Gilmore IS, Carmeliet P, Desmedt C, Malanchi I, Swinnen JV, Altea-Manzano P, Lê Cao KA, Meiser J, Yuneva M, Fendt SM
Cancer Discov
· 2026 Jul · PMID 41778850
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UNLABELLED: Cancer cells that seed in the lung require lipids often produced by alveolar type II (AT2) cells. However, whether overt metastases depend on AT2 cell-derived lipids and whether AT2 cells can be targeted to r...UNLABELLED: Cancer cells that seed in the lung require lipids often produced by alveolar type II (AT2) cells. However, whether overt metastases depend on AT2 cell-derived lipids and whether AT2 cells can be targeted to reduce metastasis growth remains unknown. We discovered that breast cancer-derived lung metastases stimulate the proliferation of AT2 cells in their vicinity and reprogram them into lipid feeder cells in mice and patients using spatial analysis. Mechanistically, the metastasis secretome activates the transcription factor sterol regulatory element-binding transcription factor 1 (SREBP-1) in AT2 cells, enhancing the expression of key de novo lipid synthesis genes, including fatty acid synthase (FASN) and glycerol-3-phosphate acyltransferase 1 (GPAM). Deleting Fasn selectively in AT2 cells or targeting FASN and GPAM systemically significantly impairs lung metastasis growth in mice. In summary, we discovered that overt metastases reprogram AT2 cells and that targeting the lipid metabolism of AT2 cells impairs metastasis growth. SIGNIFICANCE: Current therapies in oncology targeting the cancer or immune cell compartment of tumors show limited efficacy against breast cancer-derived metastases. We discovered that decreasing the lipid metabolism of lung resident AT2 cells is sufficient to impair lung metastasis growth in mice without apparent adverse effects.
Cancer Grand Challenges is an international research initiative, galvanizing the global research community to take on cancer's toughest challenges through interdisciplinary team science. In this article, we introduce our...Cancer Grand Challenges is an international research initiative, galvanizing the global research community to take on cancer's toughest challenges through interdisciplinary team science. In this article, we introduce our five new teams, each awarded up to $25 million and their creative approaches to tackle five of our latest challenges.