Li C, Hu X, Zhang Z
… +8 more, Zhu H, Wu Q, Zhang H, Wang L, Liu Y, Wang J, Liu L, Hu Q
Cancer Lett
· 2026 Aug · PMID 42134490
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Cholangiocarcinoma is a highly malignant tumor with an increasing incidence around the world. Discovery of novel molecular targets and effective therapies for cholangiocarcinoma are urgently needed. Palmitoylation is a r...Cholangiocarcinoma is a highly malignant tumor with an increasing incidence around the world. Discovery of novel molecular targets and effective therapies for cholangiocarcinoma are urgently needed. Palmitoylation is a reversible lipid modification mainly catalyzed by ZDHHC family palmitoyltransferases. However, its function and underlying mechanisms in cholangiocarcinoma remain poorly understood. Here, we found that protein palmitoylation levels and ZDHHC5 expression were upregulated in cholangiocarcinoma. Knockdown of ZDHHC5 inhibited the growth of cholangiocarcinoma. Mechanistically, ZDHHC5 modulates the activity of MAPK signaling pathway by regulating palmitoylation of BRAF at Cys194/195. Palmitoylation facilitates the membrane localization of BRAF and stabilizes BRAF protein. Either knockdown of ZDHHC5 or disruption of palmitoylation sites of BRAF inhibited ERK signaling. Furthermore, we found that cholangiocarcinoma cells expressing high levels of ZDHHC5 exhibited increased activities of MAPK signaling pathway and increased sensitivities to MAPK signaling pathway inhibitors. This study identifies a previously unknown ZDHHC5-BRAF-ERK axis that promotes the growth of cholangiocarcinoma and represents a potential crucial role in therapeutic.
Zhu J, Kong F, Guo D
… +3 more, Zhang T, Yang Z, Yang T
Cancer Lett
· 2026 Aug · PMID 42105804
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Epigenetic dysregulation drives tumor progression and therapeutic resistance, creating a critical need for targeted modulators. Protopanaxadiol (PPD) type ginsenosides, triterpenoid saponins from Panax ginseng, have emer...Epigenetic dysregulation drives tumor progression and therapeutic resistance, creating a critical need for targeted modulators. Protopanaxadiol (PPD) type ginsenosides, triterpenoid saponins from Panax ginseng, have emerged as promising natural epigenetic regulators, but their clinical translation is limited by poor bioavailability and context dependent activity. Preclinical and early clinical evidence is synthesized here to elucidate the mechanistic underpinnings and translational potential of these agents.Structurally distinct ginsenosides converge on conserved epigenetic enzyme families with tumor specific isoform selectivity: one ginsenoside modulates DNA methyltransferases (DNMTs) across ovarian, renal, and liver cancers; another selectively targets DNMTs and histone deacetylases (HDACs) in colorectal cancer (CRC); a third modulates HDACs and RNA modifiers in leukemia and breast cancer. These interventions reactivate silenced tumor suppressors, suppress epithelial mesenchymal transition (EMT), reverse metabolic reprogramming, and remodel the tumor immune microenvironment. Highly-glycosylated ginsenosides act indirectly via upstream signaling, while low-glycosylated metabolites exhibit superior bioavailability. Key mechanistic principles include family level epigenetic convergence, multi-enzyme co-regulation, and functional complementarity. Clinical translation is hindered by subtherapeutic intratumoral accumulation, lack of biomarker guided studies, and RNA modifier dependency variability. Ginsenosides represent a pharmacologically unique class of epigenetic modulators, with precision oncology potential when paired with delivery optimization and epigenetic biomarker stratification.
Hudson C, Krattli RP, El-Khatib SM
… +11 more, Vagadia AR, Do AH, Madan S, Usmani MT, Nguyen T, Swami D, Piltti KM, Thompson LM, Cummings BJ, Anderson AJ, Acharya MM
Cancer Lett
· 2026 Aug · PMID 42103073
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Cranial radiation therapy (RT) with concomitant and adjuvant temozolomide (TMZ; Stupp protocol) prolongs glioma survival but frequently results in persistent cognitive impairment. Human neural stem cell (hNSC)-derived ex...Cranial radiation therapy (RT) with concomitant and adjuvant temozolomide (TMZ; Stupp protocol) prolongs glioma survival but frequently results in persistent cognitive impairment. Human neural stem cell (hNSC)-derived extracellular vesicles (EVs) are a promising acellular therapy whose bioactive cargo can modulate neuroinflammation and synaptic integrity. We evaluated two EVs derived from GMP-grade hNSCs (Shef6 and UCI-191) in syngeneic glioma-bearing and non-tumor adult mice treated with fractionated cranial RT (3 × 8.67 Gy) together with concomitant low-dose (25 mg/kg) and adjuvant high-dose (66.7 mg/kg, intraperitoneal) TMZ. EV administration improved memory performance in RT-TMZ-exposed mice and, notably, Shef6-EVs also extended survival in glioma-bearing mice in the absence of chemoradiotherapy. Immunofluorescence analyses demonstrated attenuated gliosis and preservation of synaptic integrity in EV-treated RT-TMZ-exposed brains, while transcriptomic profiling identified distinct neuroprotective gene expression pathways associated with each EV source. Critically, neither Shef6 nor UCI-191 EVs diminished or interfered with the anti-tumor efficacy of RT-TMZ. These data support hNSC-derived EVs as a translational strategy to mitigate treatment-related neurotoxicity while preserving oncologic benefit in a clinically relevant glioma model.
Zhao J, Li M, Zhang Q
… +9 more, Li B, Qi Y, Gao Z, Wang Q, Zhao R, Zhao H, Zhang K, Xue H, Li G
Cancer Lett
· 2026 Aug · PMID 42097495
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Glioblastoma (GBM) cells eliminate temozolomide (TMZ) through extracellular vesicles (EVs), a resistance mechanism independent of DNA damage repair that markedly reduces intracellular drug concentration. However, strateg...Glioblastoma (GBM) cells eliminate temozolomide (TMZ) through extracellular vesicles (EVs), a resistance mechanism independent of DNA damage repair that markedly reduces intracellular drug concentration. However, strategies to block this efflux pathway remain poorly explored. Levetiracetam (LEV), a first-line antiepileptic for GBM patients, suppresses seizures by inhibiting synaptic vesicle release, but its potential role in chemotherapeutic efflux has not been investigated. Chemical proteomics identified RAB5A and CD63 as novel LEV-binding targets, and analyses of TCGA datasets further supported their clinical relevance. Mechanistic studies combining co-immunoprecipitation, immunofluorescence, and in silico modeling revealed LEV-mediated disruption of endosomal trafficking and membrane fusion, thereby inhibiting TMZ efflux. Nanoparticle tracking analysis and electron microscopy were used to evaluate EV release, while LC-MS/MS was employed to quantify TMZ at the subcellular and intratumoral levels. Orthotopic GBM models were used to evaluate therapeutic efficacy. RAB5A and CD63 were identified as dual mediators of LEV activity. LEV competitively bound RAB5A, impairing endosomal maturation and TMZ trafficking. LEV also disrupted CD63-RAB35 interaction, promoting RAB35 proteasomal degradation and suppressing plasma membrane fusion. Collectively, LEV reduced TMZ efflux and synergistically enhanced TMZ cytotoxicity in vitro, while in orthotopic models the combination therapy inhibited tumor growth, was accompanied by immune microenvironment remodeling, and prolonged survival.
Ruan Q, Tan YR, Kim M
… +5 more, Li D, Bridle K, O'Rourke T, Crawford D, Liang X
Cancer Lett
· 2026 Aug · PMID 42097494
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Cancer-associated fibroblasts (CAFs) are central players in the tumour microenvironment (TME) of primary liver cancer, influencing both cancer progression and treatment response. Studies involving single-cell RNA sequenc...Cancer-associated fibroblasts (CAFs) are central players in the tumour microenvironment (TME) of primary liver cancer, influencing both cancer progression and treatment response. Studies involving single-cell RNA sequencing and spatial multi-omics have significantly expanded our understanding of CAF heterogeneity and functional diversity, although consolidated markers to identify CAF subtypes and therapy-dependent plasticity remain largely unknown. In this review, CAF subpopulations, including their markers and functions, are comprehensively summarised in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. The spatial distribution of CAF subtypes from tumour core to boundary correlates with their phenotypes and functions. We focus on mapping dynamic changes of CAF subtypes in response to therapy, including chemotherapy and immunotherapy, and how these changes influence treatment response and prognosis in liver cancer. Finally, we discuss key challenges in targeting specific CAF subtypes and general CAF activation pathways in current clinical trials. This review provides a holistic view of the current and future landscape of CAF-targeting and CAF-regulating strategies in combination with standard-of-care treatments for liver cancer.
Huang Y, Liu X, Chen Y
… +5 more, Zhang H, Zhang J, Fu YX, Yang X, Yang Z
Cancer Lett
· 2026 Aug · PMID 42097493
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Adoptive cell therapy (ACT) against solid tumors is constrained by tumor heterogeneity, immunosuppressive microenvironments, and insufficient T cell potency and persistence. Although IL-12 has long been recognized as a p...Adoptive cell therapy (ACT) against solid tumors is constrained by tumor heterogeneity, immunosuppressive microenvironments, and insufficient T cell potency and persistence. Although IL-12 has long been recognized as a potent enhancer of T-cell immunity, its clinical application has been hindered by systemic toxicity and the lack of a strategy to harness its benefits without chronic exposure. Here, we show that ex vivo IL-12 preconditioning programs tumor-specific T cells with increased antigen sensitivity, yielding superior antitumor activity compared with IL-7/IL-15. Systemic delivery of Pro-IL-12 further rejuvenates exhausted CD8 tumor-infiltrating lymphocytes (TILs) by restoring IL-2 hypersensitivity, sustaining persistence, and strengthening effector machinery. When combined with ACT, a single dose of Pro-IL-12 reinstated IFN-γ production in exhausted TILs and doubled intratumoral T-cell accumulation via upregulation of IL-2Rα and increased IL-2 sensitivity. Pro-IL-12 markedly improved therapeutic outcomes, inducing durable complete tumor regression, promoting antigen spreading, and establishing long-term immune memory that prevented relapse from antigen-loss tumor. Across multiple xenograft models, including pancreatic cancer, lymphoma and triple negative breast cancer, distinct human CAR-T products paired with Pro-IL-12 enhanced tumor eradication without cytokine release syndrome. Together, these findings establish precision delivery of IL-12 as a translatable strategy that harnesses known IL-12 biology to achieve robust antitumor efficacy without systemic toxicity.
Qin G, Pan P, Qin Y
… +8 more, Wei R, Zhao Y, Fu Q, Yu H, Liu J, Wu H, Liu Z, Zhou Y
Cancer Lett
· 2026 Aug · PMID 42097492
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RNF43 is frequently inactivated by mutations in pancreatic ductal adenocarcinoma (PDAC), but the molecular mechanisms and therapeutic vulnerabilities associated with RNF43 loss remain poorly defined. Here, we demonstrate...RNF43 is frequently inactivated by mutations in pancreatic ductal adenocarcinoma (PDAC), but the molecular mechanisms and therapeutic vulnerabilities associated with RNF43 loss remain poorly defined. Here, we demonstrate that RNF43 functions as an E3 ubiquitin ligase targeting YBX1 for degradation, thereby suppressing mitochondrial oxidative phosphorylation (OXPHOS). In RNF43-deficient PDAC models, stabilized YBX1 activates MYC through dual mechanisms-enhancing MYC mRNA stability via IGF2BP1 and physically interacting with c-Myc protein-leading to transcriptional upregulation of IDH2 and IDH3A and subsequent OXPHOS activation. Importantly, RNF43 loss conferred sensitivity to OXPHOS inhibition both in vitro and in vivo. Treatment with the OXPHOS inhibitor IACS-010759 suppressed the proliferation, migration, invasion, and metastasis of RNF43-mutant tumors. Our findings identify a RNF43-YBX1-MYC signaling axis associated with metabolic reprogramming in pancreatic cancer and suggest that OXPHOS inhibition may represent a potential therapeutic vulnerability in tumors with RNF43-inactivating mutations.
Song SJ, Wang L, Li L
… +5 more, Bai SH, Zhu XL, Zhang XL, Deng CH, Han ZG
Cancer Lett
· 2026 Aug · PMID 42097491
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ARID1A is frequently mutated in non-tumorous human tissues and various cancers. However, its role in metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC) onset and progression remain...ARID1A is frequently mutated in non-tumorous human tissues and various cancers. However, its role in metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC) onset and progression remains controversial. Given the critical role of the gut-liver axis in MASH and HCC, we hypothesized that the gut microbiota might contribute to ARID1A deficiency-induced liver diseases. Here, we demonstrate that liver-specific Arid1a deficiency drives MASH/HCC development through dysregulated bile acid metabolism and gut microbiota restructuring. Gut microbiota depletion using an antibiotic cocktail attenuates MASH progression and reduces HCC incidence in liver-specific Arid1a-deficient mice. While lipopolysaccharide (LPS) accumulation due to gut barrier dysfunction promotes HCC progression, it does not significantly affect MASH activity or tumor initiation in Arid1a-deficient mice. Mechanistically, ARID1A deficiency reduces chromatin accessibility and impairs SWI/SNF complex binding at the promoter of nuclear receptor FXR, which governs bile acid homeostasis, suppressing FXR transcription. Further analyses in Arid1a-deficient mice reveal altered gut microbiota composition enriched in bile salt hydrolase (BSH) genes and bile acid profiles showing elevated levels of the secondary bile acid taurodeoxycholic acid (TDCA). When administered to mice, TDCA exacerbates liver inflammation and fibrosis specifically in Arid1a-deficient mice by promoting neutrophil infiltration and hepatic stellate cell activation. Therapeutic interventions including vancomycin to eliminate bile acid-metabolizing bacteria, obeticholic acid to activate Fxr, and cholestyramine to excrete bile acids substantially ameliorate MASH pathology in Arid1a-deficient mice. Collectively, our findings establish the ARID1A-FXR-bile acid-gut microbiota axis as a pathogenic driver of MASH and HCC, offering mechanism-based therapeutic strategies for patients with ARID1A mutations.
Peng R, Zhang J, Zhang C
… +11 more, Su B, Fan S, Chen Y, Wang Q, Jiang G, Ding L, Jin X, Wang L, Cao J, Jin S, Bai D
Cancer Lett
· 2026 Aug · PMID 42097490
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Immune checkpoint inhibitors (ICIs) demonstrate therapeutic benefits in advanced hepatocellular carcinoma (HCC), yet most patients exhibit limited responses to anti-PD-1 therapy and the molecular basis underlying this re...Immune checkpoint inhibitors (ICIs) demonstrate therapeutic benefits in advanced hepatocellular carcinoma (HCC), yet most patients exhibit limited responses to anti-PD-1 therapy and the molecular basis underlying this resistance remains largely undefined. Here, we identified the circular RNA SPECC1 (circSPECC1) as a regulator of antigen presentation and a crucial factor influencing the efficacy of anti-PD-1 therapy. circSPECC1 was significantly elevated in tumor tissues of HCC patients showing resistance to anti-PD-1 therapy and correlated with diminished intratumoral CD8 T-cell infiltration. Elevated circSPECC1 levels facilitated tumor progression and impaired the therapeutic efficacy of anti-PD-1 treatment. Overexpression of circSPECC1 in cancer cells suppressed the proliferation and cytotoxic activity of CD8 T cells both in vitro and in vivo. Mechanistically, circSPECC1 bound to the peptide-loading complex (PLC) chaperone ERP57 and disrupted its interaction with TAPBP (TAP binding Protein), thereby destabilizing PLC integrity. This aberrant interaction redirected MHC-I toward ER-associated degradation (ERAD), suppressing surface antigen presentation and impairing CD8 T-cell activation. Importantly, targeted silencing of circSPECC1 using a PEG-PEI-folate nanosystem encapsulating si-circSPECC1 significantly restored sensitivity both murine and patient-derived xenograft HCC models to PD-1 blockade. In summary, these findings uncover a novel circRNA-guided ERAD of MHC-I mechanism that impairs antitumor immunity and highlight circSPECC1 as a promising therapeutic target to overcome immunotherapy resistance.
Amara CS, Piyarathna DWB, Kamal AHM
… +50 more, Chan YS, Kami Reddy KR, Ambati CSR, Hassan MK, Shriwas P, Gandhi T, Jain A, Gangnus T, Popli P, Borkar R, Kang SW, Summers SL, Putluri V, Grimm SL, Venkatesh S, Song N, Seeley EH, Hedlich-Dwyer J, Chen SH, Mahajan NP, Jain AK, Dobrolecki LE, Wells GA, Villanueva H, Li J, Liu X, Bollag RJ, Malovannaya A, Jung SY, Lee HS, Asangani IA, Terris MK, Creighton CJ, Ballester LY, Karanam B, Liu S, Lee M, Raju RR, Siddiqui MM, Eberlin LS, Kommagani R, Sreekumar A, Gao J, Young NL, Hodges HC, Coarfa C, Gassman NR, Lerner SP, Lotan Y, Putluri N
Cancer Lett
· 2026 Aug · PMID 42092682
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Cigarette smoke promotes bladder tumor growth by enhancing cancer cell survival and proliferation through smoke mediated carcinogens. FASN, a key enzyme in fatty acid synthesis, is dysregulated in many cancers and correl...Cigarette smoke promotes bladder tumor growth by enhancing cancer cell survival and proliferation through smoke mediated carcinogens. FASN, a key enzyme in fatty acid synthesis, is dysregulated in many cancers and correlates with aggressive phenotypes. In this study, we demonstrate elevated fatty acid levels and FASN specifically in smokers with bladder cancer. Elevated FASN under smoke exposure imparted epigenetic alterations, particularly histone acetylation, impacts DNA repair and DNA-binding transcription factors which regulate metabolic pathways. Under cigarette smoke, bladder cancer cells undergo a metabolic shift, utilizing glutamine as a major carbon source through reductive carboxylation to fuel fatty acid biosynthesis via FASN. Genetic and pharmacological inhibition of FASN significantly reduced tumor growth in a chicken embryo Chorio-allantoic Membrane model exposed to smoke. FASN inhibitors such as TVB-2640, currently in clinical trials, may represent an effective therapeutic strategy for smokers with bladder cancer exhibiting high FASN levels.
Zarzuela L, López-Cepero IG, Rattigan KM
… +14 more, Reina-Bando A, Martín-Montalvo J, Sierra-Párraga JM, Sánchez-Escabias E, Morillo-Huesca M, Oltra SS, Ceballos-Chávez M, Capilla-González V, Moreno-Bueno G, Murdoch PDS, Reyes JC, Helgason GV, Tomé M, Durán RV
Cancer Lett
· 2026 Aug · PMID 42092681
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Therapy resistance is a major limitation in therapeutic efficacy for glioblastoma (GBM) patients, positioning GBM among the deadliest tumor types. In this work, we have dissected resistance mechanisms in GBM, which resul...Therapy resistance is a major limitation in therapeutic efficacy for glioblastoma (GBM) patients, positioning GBM among the deadliest tumor types. In this work, we have dissected resistance mechanisms in GBM, which resulted in the identification of FGFR1 pathway as a major controller of the signaling and metabolic rewiring associated to temozolomide (TMZ) resistance. Hence, in FGFR1-positive, p53 WT GBM cells, FGFR1 controls a p53-mediated cell cycle arrest to allow DNA repair in response to TMZ. FGFR1 also regulates a complete metabolic rewiring promoting lipid catabolism and preventing lipid peroxidation. Indeed, FGFR1 inhibition completely abolishes this signaling and metabolic reprograming, restoring sensitivity to TMZ. Our results also indicated a correlation of FGFR1 with poor prognosis in GBM patients, and validated the dual treatment with TMZ and FGFR1 inhibitors as an efficient strategy to induce tumor cell death in FGFR1-positive, p53 WT pre-clinical animal GBM models. These data position FGFR1 as a promising candidate for future clinical evaluation to limit therapy resistance to TMZ in FGFR1-positive GBM patients.
Li Z, Sun X, Zheng J
… +3 more, Sun X, Yang L, Xing L
Cancer Lett
· 2026 Aug · PMID 42092680
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Triple-negative breast cancer (TNBC) exhibits robust self-regulatory mechanisms against harsh microenvironmental stress, yet the precise molecular drivers remain elusive. Here, we identified circSCLT1 as a novel circular...Triple-negative breast cancer (TNBC) exhibits robust self-regulatory mechanisms against harsh microenvironmental stress, yet the precise molecular drivers remain elusive. Here, we identified circSCLT1 as a novel circular RNA with energy stress-responsive properties. Systematic in vitro and in vivo assays demonstrated that circSCLT1 promotes TNBC metastasis and radioresistance. Mechanistically, energy stress triggers HNRNPA1-dependent circSCLT1 biogenesis. Cytoplasmic circSCLT1 scaffolds a ternary complex with HNRNPA1 and CSDE1, blocking HNRNPA1 nuclear translocation and stabilizing IL1B via binding to its coding sequence (CDS). Additionally, the circSCLT1-containing complex displaces the E3 ubiquitin ligase TRIM25 from CSDE1 and redirects it toward TIAL1, thereby inducing K48-linked polyubiquitination and proteasomal degradation of TIAL1. Furthermore, circSCLT1 suppresses arginine dimethylation of HNRNPA1 by reinforcing the binding between CSDE1 and HNRNPA1, which in turn facilitates stress granule (SG) assembly under severe energy stress. These circSCLT1/HNRNPA1/CSDE1-containing SGs shield IL1B from autophagy-mediated degradation. Collectively, these actions amplify IL1B/NF-κB signaling, sustaining pro-survival networks that drive metastasis and radioresistance. Importantly, pharmacological inhibition of IL-1β secretion using disulfiram (DSF) synergizes with circSCLT1 silencing to markedly suppress tumor progression and extend survival in preclinical TNBC models. Our findings elucidate the oncogenic role of circSCLT1 in TNBC and underscore its potential as a novel therapeutic target, providing a rationale for combining IL-1β inhibition with circSCLT1-targeted therapy.
Cancer Lett
· 2026 Aug · PMID 42081964
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Triple negative breast cancer (TNBC), characterised by the lack of progesterone receptor, oestrogen receptor and HER2 overexpression, is the most aggressive breast cancer subtype and is typically associated with high rat...Triple negative breast cancer (TNBC), characterised by the lack of progesterone receptor, oestrogen receptor and HER2 overexpression, is the most aggressive breast cancer subtype and is typically associated with high rates of metastasis, recurrence and mortality. Despite recent advances in treatment options, such as the use of PARP inhibitors, immune checkpoint inhibitors and antibody-drug conjugates, lasting clinical benefit is limited, particularly in advanced disease. A key driver of relapse in TNBC is extensive inter- and intratumoral heterogeneity, largely sustained by self-renewing cancer stem cell (CSC) populations. These cells exhibit enhanced plasticity, immune evasion and resistance to cytotoxic drugs, enabling treatment failure and relapse. Growing evidence implicates aberrant activation of mitogen activated protein kinase (MAPK) signalling in CSC maintenance, epithelial-mesenchymal transition (EMT) and resistance to therapy in TNBC. While MAPK pathway inhibitors show limited efficacy in monotherapy, preclinical and clinical data suggest that their integration with existing treatment strategies may enhance therapeutic robustness, delay resistance and reduce recurrence. Targeting MAPK, in combination with other drugs that restrain CSC plasticity could represent a promising strategy to improve long-term outcomes in TNBC.
Wang J, Luo W, Zhang M
… +13 more, Wang Y, Ye L, Qiu JD, Liu Y, Weng G, Liu T, Cao Z, Yang G, Huang H, Xiao J, You L, Zhang T, Zhao Y
Cancer Lett
· 2026 Aug · PMID 42081963
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Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human cancers, mostly due to its insidious onset that consequently leads to diagnosis at advanced stages. The complex biology of PDAC limits effectiv...Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human cancers, mostly due to its insidious onset that consequently leads to diagnosis at advanced stages. The complex biology of PDAC limits effective therapeutic options, yet over 90% of cases harbor KRAS mutations, making it a compelling therapeutic target. KRAS had a notorious history of being "undruggable." Emerging novel inhibitors, however, have fundamentally shifted this paradigm by demonstrating the possibility of direct KRAS targeting. Although promising in preclinical efficacy, the clinical benefit of these inhibitors was frequently curtailed by rapid and heterogeneous resistance due to the intrinsic complexity of PDAC. Concurrently, building on structure-based drug discovery, artificial intelligence (AI) is now infusing this traditional workflow with dynamic and extensive enhancements. AI-enabled approaches in molecular biology-including high-accuracy protein structure prediction, large-scale virtual screening, and the uprising of generative molecular design-have accelerated the discovery of potent and selective molecular structures. Comprehensive hybrid models and quantum-level data processing enabled the exploration of previously latent chemical spaces, thereby creating more opportunities for the search for effective PDAC therapies. Discussions of progress in KRAS inhibitors and in AI drug discovery are rising but remain largely in parallel. As a result, this review aims to bridge these two exciting fields together. Through discussions of novel strategies to target KRAS in PDAC, emerging paradigms to address KRAS resistance in clinical trials, and current innovations in AI algorithms for molecule screening and design, we hope to underscore the unique challenges and prospects of leveraging artificial intelligence to accelerate the discovery of effective therapies for PDAC.
Kakkat S, Suman P, Goswami S
… +11 more, Kola B, Bruno KA, Frankel WL, Basu S, Turbat-Herrera EA, Ramirez-Alcantara V, Heslin MJ, Andrews JF, Pramanik P, Sarkar C, Chakroborty D
Cancer Lett
· 2026 Aug · PMID 42081962
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Cell-Cell adhesion maintained by tight junctions (TJs) is essential for epithelial integrity; loss of TJs correlates with poor prognosis, metastasis, and adverse clinical outcome in gastric cancer (GC). Restoring TJ inte...Cell-Cell adhesion maintained by tight junctions (TJs) is essential for epithelial integrity; loss of TJs correlates with poor prognosis, metastasis, and adverse clinical outcome in gastric cancer (GC). Restoring TJ integrity is therefore considered a promising therapeutic strategy in GC. The study identifies the stomach renin angiotensin system (stRAS) as a crucial regulator of TJ function in GC. Using integrative analysis of GC patient tissues, human GC cell lines, and orthotopic GC xenograft models, here we show that angiotensin II (ATII), the principal effector peptide of stRAS, drives TJ disassembly through an autocrine loop involving angiotensin receptor type 1 (AT1R) expressed on GC cells. Both ATII and AT1R are overexpressed in GC, where they suppress the expression of key TJ proteins. By analyzing global RNA-sequencing (RNA-seq) data and performing CRISPR/Cas9 gene deletion, chromatin immunoprecipitation, and functional assays, we mechanistically reveal that ATII, which is predominantly produced by cancer cells within the tumor microenvironment (TME), inhibits the expression of krüppel-like factor 4 (KLF4), a transcription factor crucial for the transcription of key TJ genes (CLDN1, 3, 4, and TJP1), leading to reduced synthesis of TJ proteins via AT1R expressed on cancer cells. Notably, the study demonstrates the effectiveness of pharmacological inhibition of AT1R with clinically established AT1R antagonists in preventing GC growth and metastasis by restoring TJ stability in vivo. These findings delineate a previously unrecognized role for ATII in governing TJ disassembly in GC and highlight the ATII/AT1R axis as a promising therapeutic target.
Kang X, Lei G, Hou X
… +9 more, Du Y, Xu M, Xue C, Liu D, Jia S, Shan J, Tang C, Xu X, Xu A
Cancer Lett
· 2026 Sep · PMID 42069175
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Cancer stemness drives malignant progression and drug resistance in hepatocellular carcinoma (HCC). Although mitochondrial dynamics are known to influence HCC development, the precise mechanisms linking mitochondrial fun...Cancer stemness drives malignant progression and drug resistance in hepatocellular carcinoma (HCC). Although mitochondrial dynamics are known to influence HCC development, the precise mechanisms linking mitochondrial function to stemness remain largely elusive. Integrating bulk and single-cell transcriptomics, we identified Butyrophilin Subfamily 3 Member A3 (BTN3A3) as a novel oncogene driving HCC stemness. BTN3A3 depletion markedly reduced sphere formation, stemness-related gene expression, and the percentage of CD90/EpCAM cancer stem cells. Rescue experiments confirmed that BTN3A3 promotes HCC cell proliferation, migration, and invasion. Furthermore, BTN3A3 depletion sensitized HCC cells to sorafenib by inducing ROS accumulation and apoptosis. Mechanistically, mass spectrometry and Co-IP identified TOMM22 as a key mitochondrial interactor of BTN3A3. Crucially, sorafenib stress actively promotes BTN3A3 mitochondrial translocation, where it shields TOMM22 from ubiquitin-proteasome-dependent degradation. BTN3A3 deficiency led to TOMM22 depletion, mitochondrial fragmentation, and impaired oxidative phosphorylation (OXPHOS) and ATP production. Importantly, silencing TOMM22 reversed BTN3A3-mediated stemness and sorafenib resistance. In vivo orthotopic xenograft models and patient-derived organoids (PDOs) further validated that BTN3A3 correlates with stemness and malignant tumor growth. Utilizing 5E08, a pan-BTN3 monoclonal antibody, markedly suppressed tumor growth and concurrently downregulated TOMM22 expression in vivo. In conclusion, our study unveils a previously unrecognized non-immunological role for BTN3A3 in mitochondrial reprogramming. We demonstrate that BTN3A3 drives HCC stemness and drug resistance by preventing TOMM22 ubiquitination to maintain mitochondrial homeostasis. These findings position BTN3A3 as a promising therapeutic target, with the pan-BTN3 monoclonal antibody 5E08 offering a potential strategy to overcome stemness-driven malignancy and resistance in HCC patients.
Gai QJ, Wang C, Li SD
… +18 more, Pang B, Sun Q, Zhou H, Yao XY, Qin Y, Yan Q, Zhu YX, Liu ZD, Zhang S, Wang YX, Lu HM, Yao XX, Zhang SY, Zhang H, Qu MH, Luo Y, Bian XW, Wang Y
Cancer Lett
· 2026 Aug · PMID 42066836
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Glioblastoma (GBM) remains a lethal brain tumor with limited therapeutic efficacy from current standard care. The platelet-derived growth factor receptor alpha (PDGFRA) is a major oncogenic driver frequently amplified in...Glioblastoma (GBM) remains a lethal brain tumor with limited therapeutic efficacy from current standard care. The platelet-derived growth factor receptor alpha (PDGFRA) is a major oncogenic driver frequently amplified in gliomas. However, its high expression is paradoxically associated with improved prognosis in lower-grade gliomas, indicating a context-dependent role that is not fully understood. The regulatory mechanisms controlling PDGFRA protein stability represent a significant knowledge gap. In this study, we identify tripartite motif-containing 21 (TRIM21) as a previously uncharacterized E3 ubiquitin ligase for PDGFRA. We demonstrated that TRIM21 catalyzed K48-linked polyubiquitination specifically at lysine 606 of PDGFRA, directing PDGFRA for proteasomal degradation. Surprisingly, the oncogenic activity of TRIM21 was strictly dependent on PDGFRA expression. TRIM21 promoted malignant phenotypes specifically in PDGFRA-positive GBM cells, while exhibiting minimal or opposite effects in PDGFRA-negative cells. Mechanistically, TRIM21-mediated degradation of PDGFRA relieved a constitutive tumor-restraining function and simultaneously activated key downstream oncogenic pathways, including ERK, STAT3, and NF-κB, driving aggressive tumor progression. Clinically, elevated TRIM21 expression correlated with poor patient survival and confers resistance to both conventional radio-chemotherapy and the PDGFRA-targeted tyrosine kinase inhibitor imatinib in PDGFRA-high GBM. Our integrated analysis revealed an inverse correlation between TRIM21 and PDGFRA protein levels in patient specimens and highlighted TRIM21 upregulation as a feature of advanced disease. Collectively, these findings unveiled a crucial regulatory axis wherein TRIM21 switched PDGFRA from a context-dependent protective factor to an oncogenic driver and revealed TRIM21 as a prognostic biomarker and a therapeutic target for the PDGFRA-amplified subset of GBM.