Kong J, Lee I, Boecher D
… +14 more, Singhal A, Kelly MR, Moon J, Ahn CH, Ock CY, Pratt D, Kumar T, Sears TJ, Laub D, Wright S, Wall P, Carter H, Wang Z, Ideker T
Cancer Discov
· 2026 May · PMID 42188872
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While genetic sequencing is routine in cancer care, translating a tumor's complex mutation profile into actionable treatment decisions remains a central challenge. MutationProjector is pre-trained from a large corpus of...While genetic sequencing is routine in cancer care, translating a tumor's complex mutation profile into actionable treatment decisions remains a central challenge. MutationProjector is pre-trained from a large corpus of genomic alterations across 30,000+ tumors, integrated with extensive molecular knowledge. The resulting projection reveals a tumor's altered molecular pathways, facilitating model interpretation, and it accurately reconstructs held-out mutations, demonstrating model generalization. When applied to predict immunotherapy or chemotherapy resistance across multiple cancer types and cohorts, MutationProjector achieves or exceeds state-of-the-art performance in all contexts. It identifies unexpected biomarkers, including KMT2D mutation in immunotherapy sensitivity and joint alteration of SMARCA4 and STK11 in immunotherapy resistance. These results establish a unifying framework for connecting tumor genotypes to biological mechanisms and therapeutic outcomes.
New research suggests that starting a glucagon-like-peptide (GLP)-1 receptor agonist following a diagnosis of certain obesity-related cancers-namely stage I, II, or III lung, breast, colorectal, or liver cancers-may prev...New research suggests that starting a glucagon-like-peptide (GLP)-1 receptor agonist following a diagnosis of certain obesity-related cancers-namely stage I, II, or III lung, breast, colorectal, or liver cancers-may prevent them from advancing to stage IV. However, experts aren't ready to prescribe them to patients with newly diagnosed earlier stage disease without additional research confirming their value.
Patients with advanced ovarian cancer who fasted before and after chemotherapy treatments had lower insulin levels and better outcomes compared with those who ate normally, according to results from a recent study.Patients with advanced ovarian cancer who fasted before and after chemotherapy treatments had lower insulin levels and better outcomes compared with those who ate normally, according to results from a recent study.
The accelerated approval of sonrotoclax makes it the first BCL-2 inhibitor cleared for relapsed or refractory mantle cell lymphoma, offering a mechanistically distinct option for patients who have tried BTK inhibitor the...The accelerated approval of sonrotoclax makes it the first BCL-2 inhibitor cleared for relapsed or refractory mantle cell lymphoma, offering a mechanistically distinct option for patients who have tried BTK inhibitor therapy. The drug, which binds BCL-2 with more than 10-fold greater potency than venetoclax and may carry a cleaner platelet toxicity profile, is now being tested head-to-head against venetoclax in multiple phase III chronic lymphocytic leukemia trials that could reshape the treatment landscape for that disease as well.
Paul Mischel, MD, and Alice Shaw, MD, PhD, the scientific program co-chairs for the American Association for Cancer Research Annual Meeting 2026, discuss some of the most exciting topics and key scientific themes to emer...Paul Mischel, MD, and Alice Shaw, MD, PhD, the scientific program co-chairs for the American Association for Cancer Research Annual Meeting 2026, discuss some of the most exciting topics and key scientific themes to emerge from the meeting.
Elhossiny AM, Kadiyala P, Okoye JO
… +24 more, Hiraki HL, Procario MC, Giridharan T, Watkoske HR, Tannus Ruckert M, Wang J, Griffith BD, Bray AW, Mills JN, Espinoza CE, Zeller J, Peterson N, Bednar F, Zhang Y, Rao A, Lyssiotis CA, Szczepanski JM, Shi J, Deshpande A, Maitra A, Fertig EJ, Carpenter ES, Frankel TL, Pasca di Magliano M
Cancer Discov
· 2026 May · PMID 42165710
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Pancreatic intraepithelial neoplasia (PanIN) precedes pancreatic cancer, a deadly disease characterized by an extensive tumor microenvironment. How the microenvironment evolves during cancer progression is largely unknow...Pancreatic intraepithelial neoplasia (PanIN) precedes pancreatic cancer, a deadly disease characterized by an extensive tumor microenvironment. How the microenvironment evolves during cancer progression is largely unknown, as PanINs are microscopic and non-diseased pancreas samples are exceedingly rare, while adjacent normal samples are disrupted by the presence of malignancy. Leveraging donor organs and spatial technologies we mapped the evolution of PanIN to cancer. The PanIN epithelial component falls on a continuum with cancer while the PanIN microenvironment is drastically distinct. Progression to cancer is accompanied by profound geographical reorganization of myeloid cells and lymphocytes and the formation of a cancer-specific fibroblast population characterized by high levels of Smooth Muscle Actin, LRRC15 and the WNT signaling component LEF1. Together, our data show asynchronous evolution of epithelial and stromal components during pancreatic carcinogenesis. Lack of stromal reprogramming might explain why most PanINs do not progress to cancer. Compiled data available at https://pascadimagliano-lab.github.io/PancAtlas.
Chen Z, Ren X, Zhang Y
… +16 more, Kang Y, Yang Y, Xu Y, Zhou Q, Liao C, Zeng Q, Liu X, Lin R, Yang Y, Luo F, Shen S, Peng S, Li X, Long J, Xu L, Kuang M
Cancer Discov
· 2026 May · PMID 42154581
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Neutrophils are major players in innate immune immunity. However, their landscape and functions in colorectal cancer liver metastasis (CRLM) remain poorly understood. Here, using single-cell RNA sequencing and spatial-en...Neutrophils are major players in innate immune immunity. However, their landscape and functions in colorectal cancer liver metastasis (CRLM) remain poorly understood. Here, using single-cell RNA sequencing and spatial-enhanced-resolution-omics-sequencing (Stereo-seq), we provide a comprehensive transcriptional landscape of tumor-associated neutrophils (TANs) in CRLM. Our analysis reveals that a terminally differentiated pro-tumor neutrophils subset (TAN1), characterized by a glycolysis signature and a senescent phenotype, is significantly enriched in liver metastasis and associated with poor prognosis. Mechanistically, TAN1 arises from other TAN subsets through the upregulation of BHLHE40, driven by glucose deprivation in the metastatic microenvironment. Functionally, TAN1 promotes angiogenesis via VEGFA and recruits immunosuppressive macrophages through potential CCL3L1-CCR1 signaling, thereby fostering an angiogenic immunosuppressive niche. As a result, neutrophil-specific knockout of Bhlhe40 in mice significantly promotes anti-tumor immunity and suppresses tumor growth. In sum, our data uncover the critical role of BHLHE40+ senescent-like neutrophils in shaping the immunosuppressive microenvironment of CRLM.
Through machine learning, researchers have uncovered distinct spatial ecotypes in the tumor microenvironment that are broadly conserved across multiple cancers and may correlate with response to immune checkpoint blockad...Through machine learning, researchers have uncovered distinct spatial ecotypes in the tumor microenvironment that are broadly conserved across multiple cancers and may correlate with response to immune checkpoint blockade. These ecotypes are also identifiable through methylation profiling, suggesting another potential use for liquid biopsy-a way to noninvasively monitor the tumor microenvironment.
The May 1 approval of vepdegestrant, the first PROTAC drug to earn regulatory clearance, establishes targeted protein degradation as a clinically validated therapeutic modality. For patients with ESR1-mutant advanced bre...The May 1 approval of vepdegestrant, the first PROTAC drug to earn regulatory clearance, establishes targeted protein degradation as a clinically validated therapeutic modality. For patients with ESR1-mutant advanced breast cancer, it offers a new therapeutic option after standard hormone-based regimens have failed. And for the broader field, it is proof of concept for a pipeline of protein-destroying drugs that now numbers in the dozens.
Yu K, Chen J, Chu YY
… +49 more, Nair S, Crupi E, Hasanov E, Mei Y, Han X, Liu Y, Liu Y, Pei G, Peng F, Liao J, Dai E, Chu T, Cho KS, Jiang J, Yan X, Dai Y, Wang J, Zhang B, Genovese G, Putluri N, Eberlin L, Yang L, Lin C, Kwong LN, Shamsutdinova D, Wani KM, Czerniak BA, Yu W, Zhao J, Guo CC, Hansel D, Pettaway C, Pisters L, Bree K, Navai N, Lee BH, Kamat AM, Sharma P, Corn P, Jiang CY, Shah AY, Alhalabi O, Msaouel P, Siefker-Radtke AO, Logothetis CJ, Campbell MT, Lazar AJ, Gao J, Wang L
Cancer Discov
· 2026 May · PMID 42126225
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Muscle-invasive bladder cancer (MIBC) is clinically heterogeneous, and current molecular subtyping does not capture the spatial organization of tumor states and microenvironmental context. Here, we construct a spatial at...Muscle-invasive bladder cancer (MIBC) is clinically heterogeneous, and current molecular subtyping does not capture the spatial organization of tumor states and microenvironmental context. Here, we construct a spatial atlas of MIBC by integrating spatial transcriptomics from 22 tumors with matched bulk RNA and whole-exome sequencing data. We identify a continuous, spatially organized luminal-to-basal axis within individual tumors that is associated with greater chromosomal instability and transcriptional plasticity. Luminal tumor cores are enriched for FGFR3 and NECTIN4, whereas basal-like states localize toward invasive margins and are associated with elevated EGFR signaling, epithelial-mesenchymal transition, genomic instability, immune infiltration, and greater chemotherapy sensitivity. Spatial analyses further reveal lineage- and location-associated differences in tertiary lymphoid structure states. Pan-cohort analyses across over 3,000 tumors confirm conserved FGFR3-EGFR lineage exclusivity and associated immune programs. Together, these findings define a spatial framework for understanding lineage states, immune architecture, and therapeutic vulnerabilities in MIBC.
Cattaneo CM, Scardellato S, Mauri G
… +14 more, Matafora V, Ojala VK, Cannariato C, Chila R, Magnani ZI, Scheper W, Lazzari L, Voest EE, Bonini MC, Bachi A, Siena S, Marsoni S, Germano G, Bardelli A
Cancer Discov
· 2026 May · PMID 42126206
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While microsatellite-instable (MSI) colorectal cancers (CRC), reflecting mismatch repair deficiency, often respond to immune checkpoint inhibitors, microsatellite-stable (MSS) tumors remain largely resistant. This dispar...While microsatellite-instable (MSI) colorectal cancers (CRC), reflecting mismatch repair deficiency, often respond to immune checkpoint inhibitors, microsatellite-stable (MSS) tumors remain largely resistant. This disparity is typically attributed to differences in neoantigen load. However, whether antigen-independent mechanisms contribute to immune evasion in MSS-CRC remains unclear. To address this, we engineered a model in which MSI- and MSS-CRC cells express identical levels of a defined antigen recognized by TCR-engineered T cells. Despite equivalent antigen presentation, MSS tumors exhibited impaired T-cell activation, reduced cytotoxicity, and resistance to killing. We linked this immune evasion to the MSS tumor secretome, which suppressed immune responses even in immunogenic MSI cells by impairing immune synapse formation. Surfaceome profiling by mass spectrometry identified glycosylation-dependent alterations that impair immune recognition. Our findings demonstrate that MSS-CRC evades immune attack via intrinsic secretome-driven mechanisms, independent of antigenicity. Targeting glycosylation-linked suppressive pathways may restore T-cell responsiveness and improve immunotherapy efficacy in MSS-CRC.
A new analysis of tumor data from the MSK-IMPACT dataset revealed that the effects of cancer driver mutations differ based on their context, and that HLA alleles vary considerably by ancestry. Both findings have potentia...A new analysis of tumor data from the MSK-IMPACT dataset revealed that the effects of cancer driver mutations differ based on their context, and that HLA alleles vary considerably by ancestry. Both findings have potential therapeutic implications.
Wu Q, An S, Gelardi F
… +17 more, Zhang Y, Li L, Kong W, Cao M, Jia W, Xu D, Wan L, Huang G, Wang C, Hu Z, Huang J, Zhai W, Zhang J, Chiti A, Huang G, Liu J, Wei W
Cancer Discov
· 2026 May · PMID 42112793
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This single-center prospective phase II trial evaluated [18F]RCCB6 PET/CT, a CD70-targeting radiotracer, for detecting metastases in clear cell renal cell carcinoma (ccRCC). After screening 291 patients, 150 patients wit...This single-center prospective phase II trial evaluated [18F]RCCB6 PET/CT, a CD70-targeting radiotracer, for detecting metastases in clear cell renal cell carcinoma (ccRCC). After screening 291 patients, 150 patients with histologically confirmed ccRCC or suspected kidney cancer underwent imaging. Among 1,221 assessable extra-renal lesions, [18F]RCCB6 PET/CT achieved 94.2% sensitivity, 80.0% specificity, 93.1% accuracy, and 98.3% positive predictive value. In a head-to-head comparison of 99 patients with 683 lesions, [18F]RCCB6 significantly outperformed [18F]FDG PET/CT, with higher diagnostic sensitivity (90.5% vs. 41.1%) and specificity (81.4% vs. 24.3%; both P < 0.001). Compared with conventional imaging across 748 lesions, [18F]RCCB6 PET/CT also demonstrated superior sensitivity (90.8% vs. 75.1%) and specificity (81.6% vs. 56.6%). [18F]RCCB6 uptake (SUVmax) strongly correlated with CD70 expression (r = 0.843, P < 0.001). Moreover, the imaging findings changed clinical management in 58.7% of patients. [18F]RCCB6 PET/CT is a highly sensitive imaging modality for diagnosing ccRCC metastases and informing clinical decision-making.