Wu S, Liu C, Du J
… +17 more, Huang L, Ma J, Peng Z, Ling Y, Gu Y, Deng X, Zhu W, Li H, Wu M, Li D, Guo J, Liao M, He H, Li Y, Tang Y, Wang H, Li Y
Cancer Lett
· 2026 Jul · PMID 41991139
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Primary gastro-intestinal lymphomas (PGIL) are the most common extra-nodal lymphomas. Currently, existing prognostic models for gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) like the HLAMA model is lack of ri...Primary gastro-intestinal lymphomas (PGIL) are the most common extra-nodal lymphomas. Currently, existing prognostic models for gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) like the HLAMA model is lack of rigorous external validation. In this study, we conducted a multi-center retrospective investigation to establish a prognostic model for PGI-DLBCL. A total of 1 023 consecutive newly-diagnosed patients with PGIL were recruited from 9 medical centers in China. Among them, data of 462 patients with diffuse large B-cell lymphoma (DLBCL) who received R-CHOP treatment were analyzed, which was used as the training cohort. Additionally, data of 192 PGl-DLBCL patients from the other 3 medical centers were collected and used as the external validation cohort. A risk prediction model was constructed using the coefficients of weighted independent prognostic co-variates from the multi-variate analysis. It was found that patients with PGI-DLBCL receiving R-CHOP had better survival than those receiving CHOP (P < 0.001). In multi-variate analysis of the training cohort with PGI-DLBCL receiving R-CHOP, Age (P = 0.03), Lugano stage (P < 0.001), Hemoglobin (P = 0.04) and Lactic dehydrogenase (LDH) concentrations at diagnosis (P < 0.001) were significantly-associated with survival. Using these co-variates we constructed a survival prognosis nomogram model, resulting in C-statistics of 0.83 (0.79, 0.88) and 0.81 (0.73, 0.88) in the training cohort and the validation cohort, respectively. Our model, which includes 4 variables (Age, Lugano stage, LDH and Hemoglobin), is efficient in predicting survival of patients with PGI-DLBCL.
Shu F, Zhang T, Chen X
… +6 more, Lu G, Guo S, Zhang Y, Huang C, Liao W, Alan Wang Y
Cancer Lett
· 2026 Jul · PMID 41985874
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KRAS-mutant colorectal cancer (CRC) exhibits an aggressive metastatic phenotype, largely driven by TGFβ-induced epithelial-mesenchymal transition (EMT). However, the downstream effectors mediating TGFβ-driven metastasis...KRAS-mutant colorectal cancer (CRC) exhibits an aggressive metastatic phenotype, largely driven by TGFβ-induced epithelial-mesenchymal transition (EMT). However, the downstream effectors mediating TGFβ-driven metastasis in this context remain incompletely defined. This study identifies interferon regulatory factor 2 (IRF2) as a key metastasis suppressor and direct transcriptional repression target of TGFβ-SMAD2/3 signaling. IRF2 expression is markedly downregulated at invasive tumor fronts, showing a significant inverse correlation with p-SMAD2 levels and advanced metastatic stage. Single-cell trajectory analysis reveals temporal IRF2 suppression precisely coinciding with TGFβ/EMT program activation during metastatic progression. Mechanistically, SMAD2/3 complexes directly bind the IRF2 promoter to mediate repression, and IRF2 overexpression effectively reverses TGFβ1-induced invasive phenotypes in vitro. Pharmacological TGFβR1 inhibition restores IRF2 expression, slowing tumor progression and extending survival in the KRAS-driven iKAP mouse model. Furthermore, IRF2 reconstitution potently inhibits CRC cell invasion and metastasis by transcriptionally repressing EMT-related genes and enhancing anti-tumor immunity, characterized by increased CD8 T-cell infiltration and reduced regulatory T cells (Tregs). While active in various CRC contexts, the TGFβ-SMAD2/3-IRF2 axis is particularly critical in KRAS-mutant CRC, where IRF2 loss acts as a functional second hit to accelerate dissemination. These findings uncover a TGFβ-SMAD2/3-IRF2 axis governing EMT and metastatic dissemination, positioning IRF2 restoration as a promising therapeutic strategy for aggressive KRAS-mutant CRC.
Zhang S, Shi Z, Du S
… +13 more, Zhu T, Li P, Zhao R, Zhu X, Wu S, Tan Y, Xu W, Li B, Li Z, Wang K, Zhang L, Tian J, Liu Z
Cancer Lett
· 2026 Jul · PMID 41985873
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PURPOSE: Early prediction of treatment response during neoadjuvant therapy (NAT) is crucial for timely therapeutic adjustments in breast cancer. Jointly capturing dynamic tumor evolution from longitudinal imaging and tum...PURPOSE: Early prediction of treatment response during neoadjuvant therapy (NAT) is crucial for timely therapeutic adjustments in breast cancer. Jointly capturing dynamic tumor evolution from longitudinal imaging and tumor microenvironmental cues from biopsy enables improved predictive performance and fosters the development of a personalized tool to assist clinicians in managing NAT. METHODS: We proposed a multimodal framework, RePALM, which integrated clinical information, pre-NAT MRI, biopsy pathology, and post-2cycle MRI. It was developed and validated on 2604 patients from four retrospective cohorts and further evaluated in a prospective cohort of 72 patients (ChiCTR.org.cn, ChiCTR2400079698). The stepwise integration strategy enabled assessment of the incremental value of each modality. Model performance was benchmarked against radiologists in a reader study, and its predictions were further integrated with RECIST 1.1 for exploratory response stratification. Transcriptomic analysis was conducted to provide biological interpretability. RESULTS: RePALM demonstrated consistent performance across retrospective and prospective validation cohorts, with AUROC of 0.8730-0.8970 and AUPRC of 0.7450-0.8140. After two NAT cycles, RePALM identified ∼90% of non-pCR patients, enabling early consideration of surgical intervention or trial enrollment. We further demonstrated that stepwise incorporation of multimodal information markedly enhances predictive accuracy. The model also improved assessment performance for junior radiologists. RePALM-derived scores were independently prognostic for event-free survival, while transcriptomic analysis revealed enrichment of treatment-sensitivity pathways, underscoring biological plausibility. CONCLUSION: RePALM integrates longitudinal imaging and biopsy pathology to predict early NAT response, with demonstrated associations with survival and underlying biological processes, supporting its potential utility in individualized management of breast cancer.
Wei T, Zhong G, Qian J
… +8 more, Wang J, Yan Y, Shu M, Huang C, Chen Y, Zhang X, Li M, Zhang Y
Cancer Lett
· 2026 Jul · PMID 41985872
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Bone metastatic pain in lung cancer remains difficult to control and its molecular drivers are incompletely defined. Here, integrating a clinical cohort with mechanistic models, we delineate a tumor metabolism-neural epi...Bone metastatic pain in lung cancer remains difficult to control and its molecular drivers are incompletely defined. Here, integrating a clinical cohort with mechanistic models, we delineate a tumor metabolism-neural epigenetic-ion-channel axis. In patients with lung cancer bone metastases, 63% reported moderate-severe pain, and higher preoperative VAS scores associated with shorter overall survival. Single-cell RNA-sequencing of metastatic lesions demonstrated glycolysis enrichment in tumor cells from patients with higher pain, and dorsal root ganglia (DRG) from these patients exhibited stronger pan-lysine lactylation, which positively correlated with VAS. In mice, a femoral Lewis lung carcinoma model recapitulated progressive mechanical allodynia, thermal hyperalgesia, locomotor impairment, systemic hyperlactatemia, and increased DRG lactylation. Intrathecal lactate in naïve mice induced DRG lactylation and hypersensitivity, whereas intrathecal oxamate in tumor-bearing mice attenuated both, establishing a causal role for lactate signaling. CUT&Tag profiling revealed a marked gain of H3K18 lactylation at the Trpm3 promoter in tumor DRG, with concordant upregulation of Trpm3 mRNA and TRPM3 protein; Trpm3 mice displayed blunted thermal and mechanical pain behaviors. Therapeutically, CT-guided microwave ablation (MWA) of femoral tumors produced significant analgesia and functional improvement, reduced DRG H3K18 lactylation and TRPM3, and, in vitro, suppressed tumor glycolytic proteins (HK2, MCT1, GLUT1). These findings identify a targetable lactate-H3K18 lactylation-TRPM3 pathway in bone metastatic pain and support MWA as a mechanism-based palliative strategy that modulates the metabolic-epigenetic drivers of nociceptor sensitization.
Liu X, Wang Y, Cheng Y
… +16 more, Yuan X, Li Y, Lian J, Duan Y, Zheng S, Wu C, Huang G, Zhao B, Hu J, Zhang B, Xu H, Liu C, Duan L, Dong R, Hong X, Wen F
Cancer Lett
· 2026 Jul · PMID 41985871
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Distal metastasis remains a major clinical challenge in neuroblastoma (NB), the most common extracranial solid tumor in children. However, the molecular mechanisms mediating tumor-endothelial crosstalk and NB metastasis...Distal metastasis remains a major clinical challenge in neuroblastoma (NB), the most common extracranial solid tumor in children. However, the molecular mechanisms mediating tumor-endothelial crosstalk and NB metastasis remain incompletely understood. By integrating single-cell omics analyses of clinical NB samples with experimental validations, we established the molecular subtypes of NB and identified a C2 subtype marked by MYCN amplification and dual positivity for TWIST1 and TAC1 expressions. This aggressive tumor subpopulation exhibited enhanced secretion of the neuropeptide substance P (encoded by TAC1), which was regulated by the transcription factor TWIST1. TAC1 signaled to tumor-associated endothelial cells with elevated TACR1 expression, consequently leading to endothelial senescence and disrupted vascular integrity. Remarkably, TAC1 overexpression was sufficient to accelerate NB tumorigenesis, circulating tumor cell (CTC) generation and metastatic progression in vivo. Clinically, TWIST1TAC CTCs were significantly enriched in the blood samples of metastatic NB patients compared to the non-metastatic group. As a proof-of-principle study, we further demonstrated that the TACR1 antagonist aprepitant could effectively suppress endothelial senescence, tumorigenesis, and CTC-mediated metastatic progression in vivo, presenting a potential therapeutic strategy for NB patients with TAC1-TACR1 activation.
Ying XH, Zhang KY, Jiang SH
… +14 more, Chen L, Li JJ, Liu GY, Yu KD, Wu J, Di GH, Wang YY, Fan L, Hou YF, Shao ZM, Zhu XZ, Hu X, Chen C, Wang ZH
Cancer Lett
· 2026 Jul · PMID 41974248
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Neoadjuvant therapy (NAT) has emerged as a standard treatment strategy for locally advanced breast cancer (BC), yet robust biomarkers for response prediction remain elusive. Here, we established a real-world NAT cohort o...Neoadjuvant therapy (NAT) has emerged as a standard treatment strategy for locally advanced breast cancer (BC), yet robust biomarkers for response prediction remain elusive. Here, we established a real-world NAT cohort of 1161 Chinese BC patients, including 1145 cases with matched clinicopathological data and targeted sequencing, to systematically evaluate genomic features associated with NAT outcomes. We identified both cross-subtype and subtype-specific genomic associations with treatment response. PI3K-pathway alterations emerged as a consistent feature of resistance across subtypes, whereas mutations such as ERBB2 in HER2+ disease and MAP3K1 in triple-negative breast cancer were associated with subtype-specific response patterns. Regimen-level analyses further showed that some genomic associations were treatment-context dependent across chemotherapy-, endocrine-, anti-HER2-, and immunotherapy-containing regimens. Among patients with non-pathological complete response (non-pCR), genomic profiling further refined risk stratification for distant recurrence by revealing subtype-specific prognostic alterations, including TOP3B and SETD2. Furthermore, a machine-learning model integrating genomic and clinicopathological features showed favorable performance for NAT response prediction. Overall, our study provides a comprehensive genomic framework for response prediction and recurrence risk assessment, supporting more precise stratification and biomarker-guided treatment optimization in Asian breast cancer patients.
Hong L, Lee S, Frisbie L
… +10 more, Zhao Y, Skoko JJ, Merkel C, Kataura T, Korolchuk VI, Coffman LG, Lee AV, Freeman BA, Schopfer FJ, Neumann CA
Cancer Lett
· 2026 Jul · PMID 41974247
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Lack of DNA double-strand break repair efficiency exquisitely sensitizes cancers to poly-ADP ribose polymerase inhibitors (PARPi). Unfortunately, resistance to PARPi poses an insurmountable challenge for patients. Mechan...Lack of DNA double-strand break repair efficiency exquisitely sensitizes cancers to poly-ADP ribose polymerase inhibitors (PARPi). Unfortunately, resistance to PARPi poses an insurmountable challenge for patients. Mechanisms that confer insensitivity to PARPi therapy include enhanced DNA damage repair and autophagy. Natural and non-natural unsaturated fatty acid nitroalkene derivatives (NFA) show anticancer actions that sensitize TNBC cells to PARPi and other DNA-damaging treatments. We reveal that nitro-oleic acid (OA-NO) re-sensitizes PARPi-resistant TNBC cells to PARPi. RNA-seq analysis of clinically relevant mutBRCA1 PARPi-resistant TNBC cell lines exhibited upregulation in autophagy and lysosomal pathways. Bio-orthogonal analysis identified the autophagy regulator SQSTM1/p62 as a novel OA-NO target, alkylating two redox-sensitive Cys residues of p62 (Cys105 and Cys113). These Cys are essential for p62 regulation of autophagy and mimicked the effects of p62 Cys105 and Cys113Ala mutants and when alkylated by OA-NO showed impaired p62 oligomerization, degradation, and inhibition of autophagy. Combination treatment of PARPi-resistant TNBC with a PARPi and OA-NO identified the most synergistic HSA scores and inhibited p62-associated autophagy and lysosome function. These data underscore the clinical potential of OA-NO for treating PARPi-resistant TNBC patients.
Gui C, Liu J, Chen J
… +17 more, Zhou X, Feng H, Fu L, Chen Y, Zhang L, Huang H, Xu X, Shu G, Zhang C, Tang Y, Zhu J, Wang Y, Wei J, Guo J, Zeng G, Li J, Luo J
Cancer Lett
· 2026 Jul · PMID 41967697
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BACKGROUND: The role of 5-methylcytosine (m5C) RNA modification in clear cell renal cell carcinoma (ccRCC) is recognized, yet its function and regulation on circular RNAs (circRNAs) remain uncharted. This study aims to i...BACKGROUND: The role of 5-methylcytosine (m5C) RNA modification in clear cell renal cell carcinoma (ccRCC) is recognized, yet its function and regulation on circular RNAs (circRNAs) remain uncharted. This study aims to identify key m5C regulators in ccRCC, with a focus on this under-explored circRNA dimension, and to determine their clinical significance. METHODS: m5C-MeRIP-seq was performed on clinical samples. The expression and prognostic value of m5C regulators were analyzed using TCGA, ICGC, and SYSU cohort. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were employed to decipher the tumor immune microenvironment. Functional experiments were conducted in vitro and in vivo. Mechanisms were investigated via RIP, RNA pull-down, and ChIP-qPCR. A nanoparticle-based siRNA delivery system was used for therapeutic assessment. RESULTS: NSUN5 was identified as the predominant m5C methyltransferase, with high expression predicting poor survival in ccRCC. Mechanistically, NSUN5 installed an m5C modification on circPPAP2A, which was recognized and stabilized by YBX1. The NSUN5/circPPAP2A/YBX1 axis enhanced YBX1 nuclear translocation and phosphorylation, leading to transcriptional activation of HIF-2α. Clinically, NSUN5 expression correlated with HIF-2α inhibitor sensitivity. scRNA-seq and spatial transcriptomics revealed that this axis suppresses CD8 T cell infiltration by downregulating CCL5 and promotes T cell exhaustion by upregulating TGFB1, thereby fostering an immunosuppressive microenvironment. Knockdown of NSUN5 or circPPAP2A in vivo synergized with anti-PD-1 therapy, potently inhibiting tumor growth and restoring anti-tumor immunity. CONCLUSIONS: Unlike prior studies focused on mRNA, we establish the NSUN5/circPPAP2A/YBX1 axis as the first identified epigenetic circuit that coordinately activates HIF-2α signaling and induces immunosuppression in ccRCC. This dual function explains its role in conferring co-resistance to both HIF-2α-targeted therapies and anti-PD-1 immunotherapy. Therefore, targeting this axis provides a novel combinatorial strategy to overcome this dual clinical resistance.
Chen T, Lv Y, Wang J
… +5 more, Yuan Y, Xu K, Shi M, Li W, Ye B
Cancer Lett
· 2026 Jul · PMID 41966513
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Dysregulated HSP90AA1 chaperone activity is a hallmark of multiple cancers; however, its post-translational regulation in esophageal squamous cell carcinoma (ESCC) remains poorly defined. Here, we defined PRMT5-dependent...Dysregulated HSP90AA1 chaperone activity is a hallmark of multiple cancers; however, its post-translational regulation in esophageal squamous cell carcinoma (ESCC) remains poorly defined. Here, we defined PRMT5-dependent symmetric dimethylation of HSP90AA1 at arginine 182 (R182) as a critical molecular switch driving ESCC progression. HSP90AA1 physically interacted with PRMT5, and genetic or pharmacological inhibition of PRMT5 markedly reduced HSP90AA1 R182 methylation, accompanied by suppression of epithelial-mesenchymal transition (EMT) programs. HSP90AA1 depletion significantly impaired ESCC cell proliferation, migration, and invasion, inducing cell-cycle arrest and EMT reversal. In rescue experiments, re-expression of wild-type HSP90AA1 restored malignant phenotypes both in vitro and in vivo, whereas the methylation-deficient R182A mutant failed to do so. Mechanistically, R182 methylation stabilized key EMT transcription factors, thereby establishing a methylation-chaperone-EMT regulatory axis. Clinically, HSP90AA1 was markedly overexpressed in ESCC tissues and correlated with poor patient outcomes. Therapeutically, dual targeting of PRMT5 and HSP90AA1 exerted potent antitumor effects, suppressing clonogenicity and invasion in vitro and significantly reducing tumor burden in both cell-derived and patient-derived xenograft models. Collectively, these findings established the PRMT5-HSP90AA1 R182 methylation axis as a targetable vulnerability in ESCC and provided a strong rationale for biomarker-driven combinatorial therapeutic strategies.
Zhang S, Xu K, Du Y
… +5 more, Liu Z, Li H, Li B, Xie L, Zhong Y
Cancer Lett
· 2026 Jul · PMID 41966512
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Colorectal cancer (CRC) typically follows the "normal-adenoma-carcinoma" (NAC) progression, with approximately 70-90% of cases driven by an adenomatous polyposis coli (APC) mutation-dependent pathway. The Apc-mutant (Min...Colorectal cancer (CRC) typically follows the "normal-adenoma-carcinoma" (NAC) progression, with approximately 70-90% of cases driven by an adenomatous polyposis coli (APC) mutation-dependent pathway. The Apc-mutant (Min) mouse, valuable for dissecting gene function and mechanisms in CRC, provides an important basis for cross-species analyses with human data. Here, we performed a cross-species analysis of single-cell and spatial transcriptomic data across multiple stages of colorectal tissues in both humans and Min mice, constructing a spatiotemporal atlas. Our study identified key microenvironmental regulatory networks involved in CRC progression and highlighted the central role of epithelial-macrophage interactions within the tumor microenvironment. We further validated the suitability of the Min mouse as a model for the intrinsic Consensus Molecular Subtypes 2(iCMS2) microsatellite-stable (MSS) subtype of CRC. Focusing on the crosstalk between tumor-associated macrophages (TAMs) and epithelial cells, we identified the EFNA1-EPHA4 axis as a critical regulator promoting the immunosuppressive polarization of TAMs and enhancing tumor cell stemness. In addition, inhibition of EFNA1 was found to slow tumor growth. This study not only provides a systematic framework for mapping CRC correspondence between humans and mice, but also uncovers key molecular mechanisms underlying CRC progression and proposes promising therapeutic targets.
Lin R, Zhao Z, Liu Z
… +4 more, Kang J, Zhang K, Huang X, Yu Y
Cancer Lett
· 2026 Jul · PMID 41962624
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Artificial intelligence (AI) is rapidly reshaping clinical oncology, as cancer care increasingly relies on integrating heterogeneous data streams spanning radiology, digital pathology, genomics, and longitudinal electron...Artificial intelligence (AI) is rapidly reshaping clinical oncology, as cancer care increasingly relies on integrating heterogeneous data streams spanning radiology, digital pathology, genomics, and longitudinal electronic health records. However, the sheer complexity and fragmentation of these multimodal inputs remain a major bottleneck for achieving truly personalized cancer management. Recent advances in AI, including foundation models, synthetic data generation, large language models, and agents, are enabling more robust representation learning, cross-modal reasoning, and clinically actionable decision support beyond what traditional single-modality systems can provide. AI-powered platforms are now accelerating molecular subtyping, refining risk stratification, and supporting individualized therapeutic recommendations by jointly modeling imaging, tissue architecture, and molecular landscapes. Moreover, emerging virtual cell and mechanistic foundation frameworks introduce a new computational paradigm for simulating cellular responses and drug-tumor interactions, offering predictive insights for treatment design and drug discovery. Despite these breakthroughs, critical challenges persist, including limited generalizability across patient populations and centers, insufficient prospective validation, regulatory uncertainty, scalability constraints, and ethical concerns surrounding fairness, transparency, and privacy. In this review, we synthesize the latest progress in multimodal oncology AI through a translational lens, emphasizing methodological trade-offs, validation readiness, and responsible deployment frameworks. We highlight how AI is moving from performance-driven benchmarking toward clinically trustworthy precision cancer care, with transformative implications for early detection, diagnosis, therapy optimization, drug development, and clinical trial design.
Li S, Bai J, Wang X
… +4 more, Guo S, Guo X, Shang Z, Shao Z
Cancer Lett
· 2026 Jul · PMID 41962623
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The DNA sensing signaling pathway mediated by cGAS-STING has achieved significant progress in cancer therapy. However, the role of the RNA sensing signaling pathway mediated by RLRs-MAVS in cancer has been relatively und...The DNA sensing signaling pathway mediated by cGAS-STING has achieved significant progress in cancer therapy. However, the role of the RNA sensing signaling pathway mediated by RLRs-MAVS in cancer has been relatively underexplored. In this review, we first elaborate on the structural basis, activation, and regulatory mechanisms of MAVS, and examine its functional interplay with other innate immune pathways. We then comprehensively review its functions in cancer. Finally, we summarize its potential clinical applications, existing challenges, and proposed solutions. Moreover, we compare MAVS with STING across these three dimensions and find that they exhibit similarities in signaling pathways, perform analogous functions in cancer, and share comparable potential for clinical applications. Therefore, we propose that MAVS could emerge as the next STING in cancer therapy.
Leu JS, Deng H, Tran HN
… +14 more, Wei X, Abdelfattah N, Wong T, Kang R, Hashiomoto C, Leonard F, Gunalp S, Benítez Salazar JM, Maldonado JA, Cristobal CD, Lee HK, An Z, Zhang N, Yun K
Cancer Lett
· 2026 Jul · PMID 41962622
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It is estimated that ∼170,000 women in the US live with metastatic breast cancer in 2025. While multiple treatment options exist for metastatic breast tumor, none of them are curative. Here, we investigate the mechanism...It is estimated that ∼170,000 women in the US live with metastatic breast cancer in 2025. While multiple treatment options exist for metastatic breast tumor, none of them are curative. Here, we investigate the mechanism through which S100A4 promotes breast cancer metastases and report that S100A4 is a critical regulator of neutrophil infiltration into the lung to establish a premetastatic niche (PMN). We show that a novel S100A4 blocking antibody (S100A4-11) suppresses neutrophil infiltration and relieves TIGIT-mediated NK cell inhibition in the lung, leading to significantly reduced lung metastases in two different mouse models. When the treatment is initiated after the PMN formation, simulating most clinical situations, S100A4-11 treatment as a monotherapy is not sufficient to block lung metastases. However, a novel combination of anti-S100A4 and anti-TIGIT treatment significantly suppresses late-stage lung metastases by increasing CD8 T and NK cell infiltration and activation in the lung. In summary, this study provides compelling evidence that S100A4 functions systemically and locally to promote breast cancer metastases and supports developing S100A4-11 as a novel immunotherapy to suppress breast cancer metastases.
Huang X, Ma L, Lu Y
… +8 more, Cui J, Qi W, Song J, Guo J, Wang S, Fang J, Lu Z, Qiu W
Cancer Lett
· 2026 Jul · PMID 41956200
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The efficacy of tyrosine kinase inhibitor (TKI)-based systemic therapy in advanced hepatocellular carcinoma (HCC) is often limited by drug resistance, the mechanisms of which remain incompletely understood. Here, we demo...The efficacy of tyrosine kinase inhibitor (TKI)-based systemic therapy in advanced hepatocellular carcinoma (HCC) is often limited by drug resistance, the mechanisms of which remain incompletely understood. Here, we demonstrate that CD276, an immune checkpoint protein, promotes TKI resistance in HCC by reprogramming lipid metabolism. Upon TKI treatment, CD276 binds pSTAT3 and undergoes importin α/β-dependent nuclear translocation. In the nucleus, CD276 cooperates with pSTAT3 to promote CD36 transcription, thereby potentiating fatty acid uptake, lipid droplet accumulation, and mitochondrial fatty acid β-oxidation. This metabolic rewiring drives HCC proliferation and confers TKI resistance. Importantly, pharmacological inhibition of CD36 with sulfosuccinimidyl oleate sodium suppresses fatty acid uptake and tumor lipid metabolism, resensitizing resistant HCC cells to TKIs. Our findings reveal the CD276-pSTAT3-CD36 axis as a key regulator of lipid metabolic reprogramming in TKI resistance, providing a promising therapeutic target to overcome treatment resistance in HCC.
Cancer Lett
· 2026 Jul · PMID 41956199
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Colorectal cancer (CRC) is a common malignancy and a leading cause of morbidity and mortality worldwide. Taurine, a sulfur-containing amino acid derivative, has gained attention for its potential regulatory role in CRC....Colorectal cancer (CRC) is a common malignancy and a leading cause of morbidity and mortality worldwide. Taurine, a sulfur-containing amino acid derivative, has gained attention for its potential regulatory role in CRC. In addition, active metabolites, such as hydrogen sulfide produced by the interaction between taurine and intestinal microbiota, may influence CRC progression. This review systematically examines the role of the "taurine-gut microbiota" axis in the pathogenesis and treatment of CRC. We summarize the mechanisms by which taurine inhibits tumor proliferation, induces apoptosis, and enhances chemosensitivity. We also highlight its role in modulating the tumor immune microenvironment, maintaining intestinal barrier function, and preserving microbial homeostasis through microbiota-mediated metabolic regulation. Finally, we discuss translational strategies, including dietary interventions and taurine-based combination therapies, providing a new perspective for integrating taurine into CRC management.
Basappa J, Goldman AR, Lobello C
… +16 more, Wang S, Rushmore D, Melnikov O, Sen NV, Mallikarjuna VS, Jain P, Edalati M, Nelson DS, Cai KQ, Lu P, Nejati R, Borghaei H, Gupta PK, Nath K, Wellen KE, Wasik MA
Cancer Lett
· 2026 Jul · PMID 41956198
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Acetate serves as an alternative carbon source in nutrient-limited tumors, yet its role in supporting nucleotide biosynthesis remains poorly understood. Here, we identify the mitochondrial enzyme ACSS1 as a key metabolic...Acetate serves as an alternative carbon source in nutrient-limited tumors, yet its role in supporting nucleotide biosynthesis remains poorly understood. Here, we identify the mitochondrial enzyme ACSS1 as a key metabolic driver in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). ACSS1 is frequently overexpressed and catalyzes the conversion of acetate to mitochondrial acetyl-CoA, sustaining oxidative metabolism and biosynthesis under nutrient stress. Genetic silencing of ACSS1 impairs mitochondrial respiration and disrupts acetate incorporation into acetyl-CoA, TCA cycle intermediates, glutamate, and aspartate, while markedly reducing C-acetate labeling of dihydroorotate and orotate, intermediates in de novo pyrimidine synthesis. Untargeted metabolomics reveal enrichment of pyrimidine biosynthesis pathways in ACSS1-high cells. Notably, acetate or uridine supplementation rescues the growth of ACSS1-deficient cells, confirming a functional link between acetate metabolism and nucleotide synthesis. Importantly, in vivo studies using two different MCL xenografts demonstrate that ACSS1 knockdown profoundly suppresses tumor growth, indicating that ACSS1 is required not only for metabolic adaptation of lymphoma cells in vitro but also in vivo. Collectively, our results uncover an ACSS1-dependent mitochondrial acetate-pyrimidine axis that sustains lymphoma growth and represents a previously unrecognized therapeutic vulnerability.
Ma R, Zhang J, Zhang MX
… +22 more, Li Y, Yin Y, Wang LR, Ding L, Lou X, Yu YF, Ma L, Dou LP, Guo ZX, Ye F, Wang YN, Liu Y, Li LH, Liu HX, Li N, Jiang H, Jiang Q, Zhang XH, Wang Y, Xu LP, Huang XJ, Sun YQ
Cancer Lett
· 2026 Jul · PMID 41950987
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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for chronic myelomonocytic leukemia (CMML), yet the population benefit from HSCT and the optimal timing of HSCT remain contr...Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for chronic myelomonocytic leukemia (CMML), yet the population benefit from HSCT and the optimal timing of HSCT remain controversial. Current guidelines, largely based on older CPSS criteria and retrospective data, may not reflect recent advances in transplant techniques and molecular stratification systems. This multicenter retrospective analysis included 389 adult CMML patients from 14 Chinese centers (2015-2023), aiming to reassess the survival benefit of allo-HSCT in a large multicenter cohort within the molecular era. Among all patients, 145 (37.3%) underwent allo-HSCT, including 68.3% from haploidentical donors. Risk stratification was performed using CPSS, MDAPS, CPSS-mol, and MMM systems. Landmark analysis set at day 148 (median transplant interval) was used to assess the effect of time-dependent covariates on long-term survival. The entire cohort had 1-, 3-, and 5-year overall survival (OS) rates of 82.7%, 55.5%, and 46.1%, respectively. In patients ≤70 years, allo-HSCT was associated with significantly improved 3-year OS in CPSS intermediate-1 (63.4% vs. 45.4%, p = 0.038) and intermediate-2 (60.2% vs. 38.7%, p = 0.049), MDAPS intermediate-1 (69.5% vs. 47.4%, p = 0.004), intermediate-2 (60.6% vs. 30.4%, p = 0.029), and high-risk (51.4% vs. 45.0%, p = 0.022), CPSS-mol intermediate-2 (59.8% vs. 39.0%, p = 0.046), and MMM high-risk groups (65.5% vs. 10.5%, p < 0.001). Landmark analysis confirmed sustained benefit in these subgroups. Haploidentical HSCT yielded outcomes comparable to matched donors. Multivariable analysis identified HSCT as an independent favorable factor for survival (HR = 0.619, p = 0.031). These findings advocate expanding transplant eligibility through integration of molecular stratification and modern HSCT platforms, particularly haploidentical protocols.
Li J, Hu H, Xu H
… +9 more, Zhu Y, Chen W, Zhao G, Patel H, Chang H, Bai Y, Tang Z, Zhang Y, Tang W
Cancer Lett
· 2026 Jul · PMID 41946263
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Clear cell renal cell carcinoma (ccRCC) is a significant clinical challenge due to its heterogeneous nature and variable prognosis. This study aimed to evaluate the prognostic role of nucleoside transporters (NTs) in ccR...Clear cell renal cell carcinoma (ccRCC) is a significant clinical challenge due to its heterogeneous nature and variable prognosis. This study aimed to evaluate the prognostic role of nucleoside transporters (NTs) in ccRCC, elucidate the mechanisms underlying the key NT in tumor progression, and develop a targeted therapeutic strategy. Utilizing the Cancer Genome Atlas (TCGA) database, Lasso regression analysis was used for identifying NTs that significantly influenced ccRCC prognosis, which were subsequently used for constructing a risk scoring model. Furthermore, other clinicopathological risk factors were combined to construct a prognostic nomogram incorporating the risk scoring model. Univariate and multivariate Cox regression analyses revealed SLC28A1 as a key NT, and its expression was validated through bioinformatics tools, single-cell sequencing, and cellular/tissue assays. Functional assessments via knockdown and overexpression experiments indicated the role of SLC28A1 in inhibiting proliferation, migration, and invasion of ccRCC cells. In addition, its expression was affected by reactive oxygen species (ROS) and involved in arachidonic acid (AA) metabolism through regulating PLA2G12A via the MAPK signaling pathway, to promote ferroptosis. Moreover, sensitive small molecule drugs binding to SLC28A1 were screened using the Cmap database, which identified sapitinib with therapeutic potential. The efficacy of sapitinib was further enhanced through targeted nanoparticle delivery, significantly inhibiting tumor growth in both in vitro and in vivo models while ensuring biosafety. In conclusion, this research elucidates the mechanism by which SLC28A1 exerts its inhibitory effect in ccRCC and proposes a promising targeted nanotherapeutic approach, offering new insights and strategies for the management of ccRCC.
Chen R, Rajasekaran S, Xing X
… +13 more, Zhang Q, Steele SM, Wang R, Babuharisankar AP, Lee JW, Storts H, Fernandez F, Guerra-Solano M, Kumar V, Keane SC, Walker JA, Wang JJ, Miles WO
Cancer Lett
· 2026 Jul · PMID 41936857
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PD-L1 drives T cell exhaustion and tumor immune evasion and is transcriptionally induced by immune cell-derived IFN-γ. Here, we find that the RNA-binding protein PUM1 recognizes a conserved 3'UTR motif in PD-L1 and is it...PD-L1 drives T cell exhaustion and tumor immune evasion and is transcriptionally induced by immune cell-derived IFN-γ. Here, we find that the RNA-binding protein PUM1 recognizes a conserved 3'UTR motif in PD-L1 and is itself induced by IFN-γ. In PUM1-deficient cells, PD-L1 fails to accumulate with IFN-γ stimulation, revealing that IFN-γ also regulates PD-L1 through PUM1-mediated post-transcriptional mechanisms. Mechanistically, we identify HNRNPA2B1 as a direct competitor of PUM1 for PD-L1 mRNA binding, thereby controlling RNA stability and protein expression. In syngeneic colon cancer models, PUM1 deficiency reduces PD-L1, slows tumor growth, and enhances CD8 T cell infiltration, whereas HNRNPA2B1 depletion restores PD-L1 and suppresses CD8 T cells. Mutation of the endogenous PUM1-binding site similarly reduces PD-L1 and restrains tumor progression. Consistently, single-cell analysis of colorectal tumors shows PUM1 positively correlates with PD-L1 and inversely with CD8 T cell infiltration. Together, our study defines a novel IFN-γ-responsive post-transcriptional regulation that controls PD-L1 expression and tumor immune suppression.