Cancer Discov
· 2026 May · PMID 41774833
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Targeted sequencing of nearly 500 paired tumor-normal cat tissue samples, representing 13 cancers, has uncovered strong similarities with the human oncogenome, including recurrently mutated TP53 as a driver of multiple t...Targeted sequencing of nearly 500 paired tumor-normal cat tissue samples, representing 13 cancers, has uncovered strong similarities with the human oncogenome, including recurrently mutated TP53 as a driver of multiple tumor types. This is the first time the domestic feline oncogenome has been comprehensively characterized, and the human parallels support utilizing cats more frequently in comparative oncology.
A new AI model that predicts how noncoding DNA mutations alter gene regulation is helping cancer researchers identify which genetic changes drive tumor initiation and progression. Early studies show how AlphaGenome can u...A new AI model that predicts how noncoding DNA mutations alter gene regulation is helping cancer researchers identify which genetic changes drive tumor initiation and progression. Early studies show how AlphaGenome can unify multiple layers of genomic regulation into a single framework, accelerating the discovery of cancer-relevant mutations that previously required years of experimental work to decipher.
Qian ZY, Deng Y, Xi M
… +20 more, Zhang XY, Sun H, Mao M, Luo XJ, Li M, Zhang Q, Chen B, Pan YQ, Liu J, He MM, Chen HJ, Yeung CW, Zheng Y, Huang JQ, Yang M, Li ZJ, Zeng ZL, Ju HQ, Xu RH, Luo H
UNLABELLED: Esophageal squamous cell carcinoma (ESCC) exhibits heterogeneous responses to chemoimmunotherapy, with only a minority achieving durable benefit, necessitating dynamic precision monitoring. Through longitudin...UNLABELLED: Esophageal squamous cell carcinoma (ESCC) exhibits heterogeneous responses to chemoimmunotherapy, with only a minority achieving durable benefit, necessitating dynamic precision monitoring. Through longitudinal plasma metabolomics of 541 serial samples from 252 ESCORT-1st trial patients receiving chemoimmunotherapy plus 3 independent cohorts of 288 samples, we established an integrated risk assessment framework spanning the entire therapeutic continuum: (i) a baseline predictor for initial responders based on metabolite signatures; (ii) an on-treatment predictor in prognosticating long-term responders among initial ones based on treatment-induced metabolic shift patterns; and (iii) a real-time model based on dual alteration of sphingolipid and glycerophospholipid dynamically stratifying progression risk. Meanwhile, 2 dietary metabolites, garlic-derived S-allyl-L-cysteine and cruciferous vegetable-derived indole-3-carbinol, were confirmed to improve outcomes by promoting NK-cell infiltration and reversing CD8+ T-cell exhaustion. In conclusion, we provide the first metabolomic roadmap for precision chemoimmunotherapy in ESCC, unifying baseline prediction, longitudinal surveillance, and dietary modulation into a clinically actionable paradigm. SIGNIFICANCE: We established a large-scale plasma metabolomic database from patients with ESCC undergoing chemoimmunotherapy, defining the first noninvasive, comprehensive, and precise monitoring framework for treatment response prediction and risk assessment. Our findings reveal clinically actionable dietary metabolites that may serve as readily accessible adjuvants to enhance chemoimmunotherapy efficacy.
The FY2026 appropriations bill signed into law includes $47.22 billion for the NIH, a $216 million increase over FY2025, and $7.4 billion for the NCI, a $128 million boost. This is a reverse from the steep cuts that were...The FY2026 appropriations bill signed into law includes $47.22 billion for the NIH, a $216 million increase over FY2025, and $7.4 billion for the NCI, a $128 million boost. This is a reverse from the steep cuts that were proposed by the White House, but the modest increases do not keep pace with biomedical inflation. In addition, the proposed 15% on indirect costs was blocked, while forward funding provisions that pay a multiyear grant all at once are included.
Cancer Discov
· 2026 Mar · PMID 41766432
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Lung adenocarcinoma arising in individuals who have never smoked is understudied, represents a substantial global health burden, and is genomically distinct from smoking-associated disease. Zhao and colleagues have ident...Lung adenocarcinoma arising in individuals who have never smoked is understudied, represents a substantial global health burden, and is genomically distinct from smoking-associated disease. Zhao and colleagues have identified transcriptomic subtypes with prognostic value, including in stage I disease, supporting phenotypic state as an important determinant of outcome for lung adenocarcinoma in individuals who have never smoked. See related article by Zhao et al., p. 460.
Cancer Discov
· 2026 Mar · PMID 41766431
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In this issue, Takahashi, Tanaka, and colleagues provide a comprehensive genomic, transcriptomic, and spatial analysis of renal cell carcinomas (RCC) associated with end-stage renal disease. They demonstrate that the clo...In this issue, Takahashi, Tanaka, and colleagues provide a comprehensive genomic, transcriptomic, and spatial analysis of renal cell carcinomas (RCC) associated with end-stage renal disease. They demonstrate that the clonal expansion of a subset of proximal tubule cells, supported by an inflammatory microenvironment, gives rise to the cysts of acquired cystic kidney disease as well as to acquired cystic disease-associated RCC. See related article by Takahashi et al., p. 478.
Cancer Discov
· 2026 Mar · PMID 41766430
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In this issue, Köhnke, Karigane, and colleagues applied allele-specific CRISPR/Cas9 correction in human acute myeloid leukemia samples to dissect the stage-specific functions of DNA methyltransferase 3A (DNMT3A) arginine...In this issue, Köhnke, Karigane, and colleagues applied allele-specific CRISPR/Cas9 correction in human acute myeloid leukemia samples to dissect the stage-specific functions of DNA methyltransferase 3A (DNMT3A) arginine 882 (R882) mutations. They demonstrate that DNMT3A R882 mutations are required to sustain self-renewal and inflammatory programs in preleukemic cells but become largely dispensable once leukemia is established, while still influencing leukemia stem cell frequency, thereby providing a strong preclinical rationale to reconsider the therapeutic window for targeting DNMT3A-mutant clones early in leukemogenesis. See related article by Köhnke et al., p. 592.
In a small adjuvant trial of patients with early-stage triple-negative breast cancer, a personalized mRNA neoantigen vaccine induced robust, multitarget T-cell responses that persisted for years. Notably, the vaccine was...In a small adjuvant trial of patients with early-stage triple-negative breast cancer, a personalized mRNA neoantigen vaccine induced robust, multitarget T-cell responses that persisted for years. Notably, the vaccine was administered on its own, without concurrent chemotherapy or checkpoint blockade, highlighting the treatment's stand-alone potential to drive durable antitumor immunity.
Findings from a phase I study show that the p53 reactivator rezatapopt is safe and can elicit responses in patients with a range of solid tumors containing the Y220C mutation. Although the drug was ineffective in tumors...Findings from a phase I study show that the p53 reactivator rezatapopt is safe and can elicit responses in patients with a range of solid tumors containing the Y220C mutation. Although the drug was ineffective in tumors with KRAS mutations, and whether the strategy can be applied to more common missense mutations remains unclear, the findings offer proof of concept for p53 reactivation.
Ding C, Dong J, Pan Z
… +14 more, Liu S, Song Q, Yang G, Peng Y, Xie C, Huang Z, Yao W, Wu M, Zhong Y, Zhang W, Zhang Y, Wang S, Ma W, Wang Y
Cancer Discov
· 2026 Jun · PMID 41747254
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UNLABELLED: Glioblastoma (GBM) cells form neuron-to-glioma malignant synapses on neurite-like tumor microtubes (TM), driving infiltrative growth and recurrence. The mechanisms underlying coordinated cross-talk among GBM...UNLABELLED: Glioblastoma (GBM) cells form neuron-to-glioma malignant synapses on neurite-like tumor microtubes (TM), driving infiltrative growth and recurrence. The mechanisms underlying coordinated cross-talk among GBM cells and with neurons to favor malignant over normal synapses remain largely unknown. Here, we demonstrate that glioma-secreted C1QL1 is a key messenger for glioma-neuron and glioma-glioma cross-talk to drive TM expansion and malignant synapse formation. C1QL1 binds to its receptor BAI3 on neighboring neurons and GBM cells, activating RAC1-mediated cytoskeleton rearrangement to prune normal synapses and outgrow TMs, promoting malignant synapse and glioma network formation. Targeted treatment with a non-GEF-targeting, first-in-class RAC1 inhibitor rescues C1QL1-mediated synaptic pruning, inhibiting TMs and malignant synapses to impede glioma recurrence. Our findings elucidate how cross-talk among GBM cells and neurons allows infiltrating GBM cells to sculpt and integrate into the existing neural network, highlighting a therapeutic strategy against GBM recurrence through simultaneous inhibition of TMs and glioma-induced synaptic pruning. SIGNIFICANCE: Our study identifies C1QL1 as a key messenger secreted by infiltrating glioma cells, orchestrating glioma-glioma and glioma-neuron cross-talk to induce TM expansion and neural synaptic pruning, driving malignant synapse formation and recurrence through a C1QL1-BAI3-RAC1 axis. Targeting RAC1 with a non-GEF-targeting RAC1 inhibitor could impede glioma recurrence and improve survival. See related commentary by Li and Borniger, p. 1047.
Zhang F, Dong C, Chow RD
… +13 more, Xin S, He E, Feng Y, Zhu L, Mirza D, Tian X, Yang L, Zhou L, Ling X, Han Q, Fan R, Chen S, Wang G
Cancer Discov
· 2026 Jun · PMID 41747251
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UNLABELLED: The hostile tumor microenvironment (TME) remains a major challenge for cancer immunotherapy. In this study, we performed TME-targeted in vivo CRISPR activation (CRISPRa) screen to identify factors that promot...UNLABELLED: The hostile tumor microenvironment (TME) remains a major challenge for cancer immunotherapy. In this study, we performed TME-targeted in vivo CRISPR activation (CRISPRa) screen to identify factors that promote antitumor immunity, culminating in rationally designed immune gene therapy combinations. Multiplexed activation of genes encoding antigen presentation, T-cell proliferation, costimulation, and migration (APCM) leads to enhanced antitumor responses. An APCM-focused CRISPRa screen in metastatic tumors identified Cd80, Tnfsf14, Cxcl10, Tnfsf18, Tnfsf9, and Ifng as top immunostimulatory candidates. Further optimization pinpointed Tnfsf9 (4-1BBL) + Ifng + Il12b (4II) as a potent therapeutic combination. Adeno-associated virus (AAV) 4II enhanced antigen presentation, T-cell activation, proliferation, cytotoxicity, and tumor infiltration. Preconditioning the TME with AAV-4II synergized with chimeric antigen receptor (CAR) and T-cell receptor (TCR) T-cell therapies to suppress primary and metastatic solid tumors in vivo. These findings establish TME-targeted CRISPRa screening as a rapid route to develop immune gene therapy combinations against solid tumors. SIGNIFICANCE: By leveraging TME-focused in vivo CRISPRa screening, we identified immunomodulatory genes for rational AAV-based combinations that boost antitumor immunity. The optimized three-gene cocktail (4II) enhances antigen presentation and T-cell function and synergizes with adoptive T-cell therapies to improve immunotherapy efficacy in solid tumors and metastases.
Tran MA, Cho BA, Izadmehr S
… +35 more, Yoo SK, Youssef D, Anker JF, Farkas AM, Figueiredo I, Lee K, Ananthanarayanan A, Balan S, Onkar S, Banchereau R, Gupta S, Chhibber A, Wang L, Beaumont KG, Li Z, Garcia-Barros M, Bicak M, Cordon-Cardo C, Brody R, Kim-Schulze S, Yuen K, Mariathasan S, Atiq SO, Adeyelu TT, Elliott A, Barata P, McKay RR, Gnjatic S, Gonzalez-Kozlova E, Mehrazin R, Horowitz A, Sfakianos JP, Chowell D, Galsky MD, Bhardwaj N
Cancer Discov
· 2026 Jun · PMID 41747249
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UNLABELLED: Immune checkpoint blockade (ICB) has revolutionized treatment for urothelial bladder cancer, yet response rates remain limited. Inflammation promotes disease progression and treatment resistance, with macroph...UNLABELLED: Immune checkpoint blockade (ICB) has revolutionized treatment for urothelial bladder cancer, yet response rates remain limited. Inflammation promotes disease progression and treatment resistance, with macrophages shaping the tumor microenvironment (TME). Although elevated blood C-reactive protein (CRP) is associated with poor clinical outcomes in urothelial bladder cancer, its relationship to the TME remains unclear. In this study, we show that elevated plasma IL6 and CRP associate with increased tumor macrophage infiltration across multiple ICB-treated cohorts. Single-cell RNA sequencing (RNA-seq) of the largest urothelial bladder cancer atlas to date, integrated with bulk RNA-seq, identifies enrichment of immunosuppressive SPP1+ macrophages in TMEs from patients with high plasma IL6. Spatial and functional analyses demonstrate that SPP1+ macrophages suppress T-cell activity partly via IL6 signaling, whereas CXCL9+ macrophages promote T-cell activation. These findings link systemic inflammation to local immune dysfunction and define a macrophage-driven axis associated with ICB resistance and therapeutic targets to improve immunotherapy outcomes in urothelial bladder cancer. SIGNIFICANCE: Single-cell and bulk RNA-seq, spatial analyses, and functional experiments identify opposing SPP1+ and CXCL9+ macrophage programs that regulate T-cell function and ICB therapy response in bladder cancer. Elevated plasma CRP and IL6 mark SPP1+ macrophage-driven immune suppression, defining a targetable IL1β/IL6 axis that contributes to immunotherapy resistance.
Zhu L, Wang X, Cheng G
… +14 more, Lai Y, Lan L, Dong Z, You Z, Chen X, He Z, Xiao X, Zhu L, Liu R, Zhang L, Zhang S, Lin D, Wu C, Chang J
Cancer Discov
· 2026 Jul · PMID 41747244
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UNLABELLED: Neoadjuvant immunotherapy improves outcomes in esophageal squamous cell carcinoma (ESCC), yet ∼70% of patients fail to respond. Pretreatment biopsies and plasma provide critical opportunities for biomarker di...UNLABELLED: Neoadjuvant immunotherapy improves outcomes in esophageal squamous cell carcinoma (ESCC), yet ∼70% of patients fail to respond. Pretreatment biopsies and plasma provide critical opportunities for biomarker discovery. In this study, we performed plasma proteomic profiling and identified soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) as the most elevated circulating protein in nonresponders. Mechanistically, tumor cell-derived sGPNMB suppressed CD8+ T-cell receptor signaling via the SDC4-CD148 axis to induce functional exhaustion, with secretion being required for its immunosuppressive activity. Cancer-associated fibroblast-epithelial (CAF-Epi) niches promoted SOX2 upregulation in tumor cells, transcriptionally activating GPNMB expression. In humanized patient-derived xenograft models, circulating GPNMB levels predicted response to PD-1 blockade, and GPNMB inhibition synergized with therapy. Across retrospective cohorts and a prospective clinical trial, a multimodal model combining plasma GPNMB levels, CAF-Epi niche detection, and clinical-pathologic features achieved robust predictive accuracy for immunotherapy response and survival. These findings establish a spatial-circulating biomarker framework for precision ESCC immunotherapy. SIGNIFICANCE: Tumor-derived soluble GPNMB, transcriptionally activated by SOX2 within CAF-Epi niches, drives CD8+ T-cell exhaustion and resistance to PD-1 blockade in ESCC. Integrating circulating GPNMB levels with CAF-Epi niche features and clinical-pathologic factors, we develop and validate a clinically scalable multimodal model for predicting immunotherapy response.
Jain N, Shi Y, May C
… +13 more, Mitra S, Bucher P, Dobrin A, Zhao Z, Hanina S, Rajasekhar VK, Yao Y, Mansilla-Soto J, Leibold J, Leslie CS, Sánchez-Rivera FJ, Feucht J, Sadelain M
UNLABELLED: Chimeric antigen receptor (CAR) therapy has transformed the treatment landscape for hematologic malignancies, but its efficacy in solid tumors is limited, owing in part to insufficient functional persistence...UNLABELLED: Chimeric antigen receptor (CAR) therapy has transformed the treatment landscape for hematologic malignancies, but its efficacy in solid tumors is limited, owing in part to insufficient functional persistence of the engineered T cells. To elucidate the basis for their functional decline, we conducted integrated chronic in vivo and in vitro screens of 400 transcription factors, which revealed NFIL3 as a driver of CAR T-cell dysfunction. Genetic disruption of NFIL3 in CAR T cells sustains their expansion and increases cytokine production, overall restraining terminal differentiation. Loss of NFIL3 enhances CAR T-cell efficacy, improving tumor control and prolonging survival in xenograft and syngeneic mouse tumor models across different CAR designs. Under chronic stimulation, disruption of NFIL3 establishes a transcriptional state predictive of favorable clinical outcomes. Our findings underscore the power of comprehensive in vivo genetic screens integrated with multiparameter in vitro assessment and identify NFIL3 as a novel therapeutic target to enhance cancer immunotherapy. SIGNIFICANCE: This study presents a two-step screening framework, integrating an in vivo pooled guide RNA screen with a multiparameter, in vitro arrayed screen. NFIL3 emerged as the top candidate, and its disruption enhanced CAR T-cell antitumor efficacy in both hematologic malignancies and solid tumors across diverse CAR architectures.