Age-related immune decline may limit cancer immunotherapy effectiveness, particularly in patients ages 75 and older. Researchers are exploring mRNA-based immune rejuvenation and senolytics as potential solutions, with a...Age-related immune decline may limit cancer immunotherapy effectiveness, particularly in patients ages 75 and older. Researchers are exploring mRNA-based immune rejuvenation and senolytics as potential solutions, with a growing number of human trials now testing whether targeting immune aging can improve treatment response. Translating these findings more broadly will require addressing safety concerns and the complexity of human immune aging.
Based on data from the U.S. National Center for Health Statistics, researchers have found that occupation may influence the risk of cancer mortality among working adults, ages 20 to 64. Broadly speaking, men working in c...Based on data from the U.S. National Center for Health Statistics, researchers have found that occupation may influence the risk of cancer mortality among working adults, ages 20 to 64. Broadly speaking, men working in construction and extraction-for instance, roofers and mining machine operators-and women working in transportation had the highest mortality rates. Numerous factors beyond carcinogen exposure, such as job stressors leading to tobacco and alcohol use, inconsistent income, and limited health-care access could explain why.
Two recent studies of CAR T cells targeting tumor-associated macrophages have shown that "armoring" these engineered cells with the ability to express the cytokine IL12 makes them more effective at eradicating solid tumo...Two recent studies of CAR T cells targeting tumor-associated macrophages have shown that "armoring" these engineered cells with the ability to express the cytokine IL12 makes them more effective at eradicating solid tumors and leads to sustained remodeling of the immunosuppressive tumor microenvironment.
Artificial intelligence systems are beginning to function as "co-scientists" in cancer research, generating drug candidates, prioritizing immunotherapy targets, and guiding experimental design. Emerging platforms now ext...Artificial intelligence systems are beginning to function as "co-scientists" in cancer research, generating drug candidates, prioritizing immunotherapy targets, and guiding experimental design. Emerging platforms now extend beyond analysis and hypothesis generation to participate directly in laboratory workflows, signaling a shift toward AI-augmented discovery across the oncology pipeline.
A neoantigen vaccine against 209 frameshift peptides elicited strong, broad, and long-lasting immunity in people with Lynch syndrome in a phase Ib/II study, offering a novel approach for preventing the range of cancers t...A neoantigen vaccine against 209 frameshift peptides elicited strong, broad, and long-lasting immunity in people with Lynch syndrome in a phase Ib/II study, offering a novel approach for preventing the range of cancers these individuals are at an elevated risk of developing.
Wei X, Blaj C, Ali Al-Radhawi M
… +46 more, Lai LP, Maldonato BJ, Yang YC, Seu L, Gundlapalli H, Jiang L, Moreno Ayala MA, Spradlin JN, Garrick B, Cai S, Salmon A, Pham A, Bredeson S, Liang R, Helland C, Evans JW, Labrecque MP, Yu X, Song AHJ, Dinglasan N, Tran L, Kumamoto A, Grigoryan L, Malliri A, Brown KD, Carter M, Simpson KL, Crosbie PA, Galvin M, Chang S, Huang Y, Tovbis Shifrin N, Pechuan-Jorge X, Raghulan R, Zhuang Y, Coles DI, Dive C, Aronchik I, Holderfield M, Lindsay CR, Wang Z, Wang Z, Singh M, Smith JAM, Jiang J, Quintana E
Cancer Discov
· 2026 Jun · PMID 41670434
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UNLABELLED: To address RAS pathway hyperactivation and targeted therapy resistance in KRASG12C-mutant non-small cell lung cancer (NSCLC), we evaluated the potential of the RAS(ON) G12C-selective covalent inhibitor eliron...UNLABELLED: To address RAS pathway hyperactivation and targeted therapy resistance in KRASG12C-mutant non-small cell lung cancer (NSCLC), we evaluated the potential of the RAS(ON) G12C-selective covalent inhibitor elironrasib and the RAS(ON) multi-selective inhibitor daraxonrasib combination to maximize RAS pathway suppression and forestall pathway reactivation in a series of preclinical models. We demonstrate that the RAS(ON) inhibitor doublet induces profound and sustained tumor regressions and overcomes the increased RAS pathway oncogenic flux that underlies resistance to inactive state-selective KRASG12C inhibitors in NSCLC. Additionally, in immune-competent preclinical models, the RAS(ON) inhibitor doublet enhances tumor immune recognition by boosting antigen presentation and remodeling the suppressive tumor microenvironment, thus promoting immune-dependent complete regressions and sensitization of an immunorefractory model to checkpoint blockade. Collectively, these findings provide a preclinical rationale for the evaluation of a targeted RAS(ON) inhibitor doublet therapy regimen in combination with immune checkpoint blockade (ICB) in patients with KRASG12C-mutant NSCLC. SIGNIFICANCE: The combination of a RAS(ON) G12C-selective and RAS(ON) multi-selective inhibitor mitigates clinical resistance mechanisms to KRASG12C(OFF) inhibitors and enhances tumor immune recognition, overcoming ICB resistance. These preclinical findings highlight the potential for a RAS(ON) targeted therapy regimen in combination with anti-PD-(L)1 in patients with KRASG12C-mutant NSCLC. See related commentary by Molina-Arcas and Downward, p. 1044.
Perez-Villatoro F, Shabanova A, van Wagensveld L
… +32 more, Junquera A, Niemiec I, Hincapié-Otero MM, Kang Z, Falco MM, Birgin K, Wolf S, Anttila E, Anandagoda G, Casado J, Marcus E, Gaillard D, Kahelin E, Chamchougia F, Salko M, Shah S, Russo S, Chiaro J, Grönholm M, Ndika J, Kari OK, iCAN, Sonke GS, Van de Vijver KK, Fpm Kruitwagen R, van der Aa M, Virtanen A, Cerullo V, Vähärautio A, Sorger PK, Horlings HM, Färkkilä A
Cancer Discov
· 2026 Jun · PMID 41661089
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UNLABELLED: The tumor microenvironment in high-grade serous ovarian carcinoma (HGSC) is a complex network of malignant-host cell interactions, yet its orchestration remains poorly understood. We present a single-cell spa...UNLABELLED: The tumor microenvironment in high-grade serous ovarian carcinoma (HGSC) is a complex network of malignant-host cell interactions, yet its orchestration remains poorly understood. We present a single-cell spatial atlas of metastatic HGSC from 280 patients, integrating high-dimensional imaging and molecular profiling. Analyzing 929 single-cell maps, we identify spatial domains with diverse cell compositions and show that immune cell coinfiltration at the tumor-stroma interface affects clinical outcomes. Using Cell Feature Importance Identification by RAndom forest (CEFIIRA), we find that tumor cell MHC class II (MHCII) expression is a key predictor of prolonged survival. Validation with deconvoluted single-cell and two distinct spatial transcriptomic datasets, along with immunopeptidomic analysis, confirms that MHCII expression correlates with immune activation, antigen presentation, and T-cell receptor clonality. Using a patient-derived immuno-oncology platform, we demonstrate that tumor MHCII expression associates with increased CD8+ T-cell cytotoxicity after PD-1 blockade, whereas blocking MHCII inhibits this activation. Our atlas offers new insights into immune activation, potentially improving patient stratification in HGSC. SIGNIFICANCE: This study delivers the first large-scale single-cell spatial atlas of HGSC, revealing how tumor-immune organization shapes outcomes. We identify tumor-intrinsic MHCII as a key driver of local immune activation and immunotherapy responsiveness, providing a mechanistic biomarker that can immediately inform improved patient stratification and therapeutic decision-making in ovarian cancer. See related commentary by Conejo-Garcia and Dangaj Laniti, p. 1041.
Nigri J, Lan W, Fung ML
… +17 more, Kayser C, Deschênes A, Hinds J, Kaushalya S, Pawlak SA, Thalappillil JS, Nadella S, Hilmi M, Park W, Kappagantula R, Park Y, Zhao Z, Preall J, Iacobuzio-Donahue CA, Tracey KJ, Borniger JC, Tuveson DA
Cancer Discov
· 2026 May · PMID 41661076
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UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) co-opts the peripheral nervous system through nerve hypertrophy, axonogenesis, and perineural invasion, and these processes correlate with patient morbidity and mortali...UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) co-opts the peripheral nervous system through nerve hypertrophy, axonogenesis, and perineural invasion, and these processes correlate with patient morbidity and mortality. Prior work has shown that autonomic nerves directly modulate neoplastic cells in PDAC, but whether cancer-associated fibroblasts (CAF) participate in neural remodeling is unknown. Using thick tissue sections, we identified dense neo-innervation near myofibroblastic CAFs (myCAF) in preinvasive pancreatic intraepithelial neoplasms. Mechanistically, TGFβ produced during inflammation and neoplasia triggers myofibroblast formation, and myCAFs produce axon guidance molecules that recruit sympathetic nerves. Norepinephrine released by sympathetic nerves activates myofibroblast cultures in vitro, and sympathetic nerve depletion impairs stromal activation and PDAC growth in vivo. A chemogenetic model confirmed that fibroblast-specific α1-adrenergic signaling exacerbated pancreatic inflammation and neoplasia. Therefore, beyond direct epithelial effects, sympathetic nerves promote pancreatitis and PDAC by co-opting myofibroblasts and myCAFs as disease amplifiers, highlighting CAF subtype-specific stromal interactions as putative therapeutic targets. SIGNIFICANCE: Pathology-associated myofibroblasts orchestrate bidirectional cross-talk with sympathetic neurons, secreting axon guidance molecules to promote nerve infiltration in inflamed and neoplastic pancreatic tissues. Specifically, α1-adrenoreceptor activation in fibroblasts acts as a molecular switch that amplifies pancreatitis severity and accelerates tumor growth, revealing new paracrine and juxtacrine interactions for further therapeutic development. See related commentary by Hondermarck et al., p.834.
Hong J, Kohutek ZA, Zhang H
… +8 more, Lecomte N, Karnoub ER, Kappagantula R, Wood LD, O'Reilly EM, Reyngold M, Crane CH, Iacobuzio-Donahue CA
Cancer Discov
· 2026 Jun · PMID 41650466
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UNLABELLED: We performed whole-exome sequencing of 250 unique tumor tissues from 30 multi-region sampled pancreatic cancer research autopsies from patients diagnosed with advanced-stage disease. Convergent evolution with...UNLABELLED: We performed whole-exome sequencing of 250 unique tumor tissues from 30 multi-region sampled pancreatic cancer research autopsies from patients diagnosed with advanced-stage disease. Convergent evolution within the TGFβ pathway is a common feature of advanced-stage disease. However, SMAD4 inactivation is more common among de novo metastatic pancreatic ductal adenocarcinomas (PDAC), whereas inactivation of TGFβ surface receptors is more common among locally advanced nonmetastatic cancers. These differences in metastatic propensity were orthogonally validated in mice by orthotopic injections of PDAC organoids with SMAD4 versus TGFBR2 inactivation. No functionally deleterious driver gene mutations were identified that were attributed to treatment, although irradiated PDACs had significantly greater genomic complexity and distinct mutational signatures compared with PDACs managed by chemotherapy. These findings provide a high-level profile of the genetic features distinguishing locally advanced from metastatic PDAC, potentially serving as a biomarker of borderline resectable or locally advanced PDACs most likely to benefit from neoadjuvant chemoradiation. SIGNIFICANCE: This study fills an important gap in knowledge related to the characteristics of genomic alterations of advanced-stage disease. We expect that these findings will serve as a baseline reference set to identify mechanisms of resistance as novel therapies continue to become available for patients with PDAC.
Girotti MR, Pedersen M, Sanchez-Laorden B
… +12 more, Viros A, Turajlic S, Niculescu-Duvaz D, Zambon A, Sinclair J, Hayes A, Gore M, Lorigan P, Springer C, Larkin J, Jorgensen C, Marais R
Cancer Discov
· 2026 Feb · PMID 41645717
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Girotti MR, Gremel G, Lee R
… +19 more, Galvani E, Rothwell D, Viros A, Mandal AK, Jonathan Lim KH, Saturno G, Furney SJ, Baenke F, Pedersen M, Rogan J, Swan J, Smith M, Fusi A, Oudit D, Dhomen N, Brady G, Lorigan P, Dive C, Marais R
Cancer Discov
· 2026 Feb · PMID 41645716
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Cancer Discov
· 2026 Feb · PMID 41645715
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Earnshaw and colleagues discover a tumor-intrinsic mechanism driven by glucocorticoid receptor (GR) activation, in which GR downregulates glycoprotein A repetitions predominant (GARP), thereby inhibiting TGFβ signaling a...Earnshaw and colleagues discover a tumor-intrinsic mechanism driven by glucocorticoid receptor (GR) activation, in which GR downregulates glycoprotein A repetitions predominant (GARP), thereby inhibiting TGFβ signaling and releasing CD8+ T cells to exert their antitumor activity. This mechanistic insight significantly advances our understanding of how GR shapes tumor immunity and highlights new avenues for overcoming immune checkpoint blockade resistance in melanoma and other cancers. See related article by Earnshaw et al., p. 345.
Cancer Discov
· 2026 Feb · PMID 41645714
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In this issue of Cancer Discovery, Chen and colleagues demonstrate that, in preclinical models, HER2 expression level directly affects trastuzumab deruxtecan internalization and cytotoxicity, with clinical data revealing...In this issue of Cancer Discovery, Chen and colleagues demonstrate that, in preclinical models, HER2 expression level directly affects trastuzumab deruxtecan internalization and cytotoxicity, with clinical data revealing divergent target dynamics depending on whether HER2 functions as an oncogenic driver or a dispensable antigen. Together with prior preclinical and clinical evidence, these findings support a context-dependent model in which target downregulation predominates in HER2-low disease, whereas payload resistance or rare binding-site mutations may dominate resistance in HER2-addicted tumors, with important implications for antibody-drug conjugate selection and sequencing. See related article by Chen et al., p. 235.
Cancer Discov
· 2026 Feb · PMID 41645713
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Pediatric cancers are unique diseases in many aspects, including their genomic driver alterations and resulting unique biology, as well as the attendant challenges posed thereby. We focus on challenges including the need...Pediatric cancers are unique diseases in many aspects, including their genomic driver alterations and resulting unique biology, as well as the attendant challenges posed thereby. We focus on challenges including the need for increased funding to pursue novel therapy development for pediatric cancer-specific driver alterations and their testing in clinical trials, as well as the underappreciated economic impact of pediatric cancer on families and patients and on society at large.
Cancer Discov
· 2026 Feb · PMID 41645712
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Centonze and colleagues demonstrate that KRASG12D inhibition in metastatic colorectal cancer triggers rapid transcriptional reprogramming from a metastasis-associated EMP1+ state to a WNT-driven LGR5+ stem cell-like stat...Centonze and colleagues demonstrate that KRASG12D inhibition in metastatic colorectal cancer triggers rapid transcriptional reprogramming from a metastasis-associated EMP1+ state to a WNT-driven LGR5+ stem cell-like state, a plastic adaptation captured through real-time live cell imaging, revealing cell state conversion as a mechanism of therapeutic resistance that can be exploited through combinatorial targeting. See related article by Centonze et al., p. 320.