Cancer Letters[JOURNAL]
Sun
200 papers
Exosomal circFXR1 drives immune evasion and tumor progression through dual regulation of PD-L1 and mTOR signaling in gastric cancer.
Chu H, Liu X, Zhuang X … +9 more , Wang F, Evans IM, Shi Y, Wang C, Guo J, Li H, Zhou Z, Deng C, Zhang C
Cancer Lett · 2026 Sep · PMID 42217559 · Publisher ↗
Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, largely due to aggressive tumor behavior, immune evasion, and limited responsiveness to immunotherapy. Circular RNAs (circRNAs) have emer...
Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, largely due to aggressive tumor behavior, immune evasion, and limited responsiveness to immunotherapy. Circular RNAs (circRNAs) have emerged as important regulators of cancer progression; however, the roles of exosomal circRNAs in tumor-immune communication in GC remain poorly understood. Here, circRNA profiling of exosomes derived from GC tissues and matched adjacent normal tissues identified circFXR1 as an upregulated circRNA associated with poor survival and adverse clinicopathological features. Functional analyses using GC cell lines, patient-derived organoid, and multiple mouse models demonstrated that circFXR1 promotes tumor proliferation, migration, and growth both in vitro and in vivo. Mechanistically, circFXR1 interacts with miR-497-5p, thereby upregulating PD-L1 expression, which in turn impairs CD8 T cell-mediated cytotoxicity. In parallel, circFXR1 activates tumor-intrinsic mTOR signaling in a miR-497-5p-dependent manner, further enhancing malignant phenotypes. Importantly, circFXR1 is enriched in tumor-derived exosomes and transferred to recipient tumor cells and CD8 T cells, resulting in increased PD-L1 expression, impaired T cell effector function, and enhanced tumor progression. Clinically, circFXR1 expression was elevated in non-responders compared with responders to anti-PD-1 therapy. Consistently, in an NSG xenograft model with adoptive transfer of human CD8 T cells, circFXR1 overexpression attenuated the therapeutic efficacy of anti-PD-1 treatment. Collectively, these findings identify exosomal circFXR1 as a regulator linking tumor-intrinsic signaling and CD8 T cell-associated immune evasion in GC. CircFXR1 may be associated with anti-PD-1 treatment response in GC, although further validation in molecularly stratified, multi-center cohorts is required.
Vesicular QSOX1-MMP2 from inflammatory cancer-associated fibroblasts degrades the extracellular matrix to drive colorectal cancer pulmonary dissemination.
Ye T, Chen M, Hu Y … +13 more , Yang Z, Xu J, Zhang Y, Zhou S, Yu Y, Chen Y, Zhang Z, Wang M, Ruan J, Zhang W, Zhang H, Chen W, Wang W
Cancer Lett · 2026 May · PMID 42217558 · Publisher ↗
Pulmonary metastases represent a leading cause of mortality in colorectal cancer (CRC); however, the stromal mechanisms underlying metastatic colonization remain incompletely understood. Here, we show that extracellular...
Pulmonary metastases represent a leading cause of mortality in colorectal cancer (CRC); however, the stromal mechanisms underlying metastatic colonization remain incompletely understood. Here, we show that extracellular vesicles (EVs) derived from inflammatory cancer-associated fibroblasts (iCAFs) are key promoters of CRC pulmonary metastasis (CRPM). Using single-cell RNA sequencing in a CRPM mouse model, we found that iCAFs constitute the predominant fibroblast population within the metastatic niche. Their differentiation was linked to NF-κB activation and SOCS3-mediated suppression of the TGF-β-Smad2/3 signaling pathway. Proteomic analysis further revealed selective enrichment of QSOX1 in iCAF-derived EVs. Functionally, QSOX1 binds to the N-terminal signal peptide (residues 1-29) of MMP2, suggesting that it may facilitate MMP2 secretion. Consistently, QSOX1 increased MMP2 abundance in EVs and enhanced EV-associated MMP2 activity, thereby facilitating degradation of the extracellular matrix (ECM) and enhancing the invasive capacity of CRC cells. Genetic knockdown of QSOX1 using siQsox1@LuT-LNPs, or its pharmacological inhibition with Ebselen, significantly reduced the lung metastatic burden and prolonged survival in vivo. Notably, Ebselen enhanced the anti-metastatic efficacy of anti-PD-L1 therapy to further suppress CRPM without augmenting toxicity. Our results establish EV-associated QSOX1-MMP2 as a pivotal regulator of metastatic niche remodeling and propose QSOX1 targeting, either alone or in combination with immune checkpoint blockade, as a promising therapeutic approach for CRPM.
Single-cell spatial transcriptional profiling of pancreatic ductal adenocarcinoma uncovers key immune-modulating and pro-metastatic mechanisms.
Zhou J, Shi G, Dai S … +10 more , Wu S, Qian F, Wu Z, Zhang J, Yang Y, Xiao B, Lu Z, Wang Y, Feng X, Jiang K
Cancer Lett · 2026 Sep · PMID 42214806 · Publisher ↗
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by profound tumor microenvironment (TME) heterogeneity and therapeutic resistance. However, the cellular dynamics, spatial architect...
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by profound tumor microenvironment (TME) heterogeneity and therapeutic resistance. However, the cellular dynamics, spatial architecture, and molecular networks driving progression from primary tumors (PTs) to hepatic metastases (HMs) remain incompletely understood. Here, we performed high-definition single-cell spatial transcriptomics using Xenium In Situ (5K) on formalin-fixed paraffin-embedded (FFPE) matched PDAC PTs and HMs, generating a single-cell spatial atlas encompassing more than 900,000 resolved cells. Integrated analysis with single-cell RNA sequencing revealed distinct cellular composition, spatial organization, and cell-cell communication patterns between PTs and HMs. Hypoxia and genomic instability were identified as core drivers of tumor cell plasticity toward a basal-like phenotype, while cancer-associated fibroblasts (CAFs) further shaped malignant cell fate. Compared with stroma-rich PTs, HMs displayed spatial immune-stromal remodeling and formed an immunogenic invasive border with actionable therapeutic vulnerabilities. We further identified functionally specialized macrophage subsets that spatially orchestrate pro-metastatic programs: TREM2 macrophages drive tumor vascular remodeling, whereas MMP12 macrophages promote CAF-mediated extracellular matrix (ECM) reorganization to facilitate metastasis. Moreover, CXCL9/10 cells recruit and activate CD8 T cells, and ectopic expression of Cxcl9/10 significantly sensitizes PDAC to immune checkpoint blockade in immunocompetent mouse models. Collectively, our study delineates the spatially coordinated tumor-stromal-immune ecosystem that sustains PDAC progression and metastasis, unveils novel immune-modulating and pro-metastatic mechanisms, and provides targetable vulnerabilities to improve immunotherapy for metastatic PDAC.
Hypoxia drives ANGPTL4 expression in tumor-associated macrophages and promotes intrahepatic cholangiocarcinoma intrahepatic metastasis.
Lin Z, Hua H, Huang Y … +7 more , Li X, Liang Y, Yi T, Jin H, Wu J, Wan Y, Li G
Cancer Lett · 2026 May · PMID 42214805 · Publisher ↗
Intrahepatic metastasis (IM) is a critical predictor of poor prognosis in intrahepatic cholangiocarcinoma (iCCA), yet the tumor microenvironmental mechanisms driving this process remain poorly understood. By integrating...
Intrahepatic metastasis (IM) is a critical predictor of poor prognosis in intrahepatic cholangiocarcinoma (iCCA), yet the tumor microenvironmental mechanisms driving this process remain poorly understood. By integrating single-cell RNA sequencing data from 15 iCCA samples with a public transcriptomic cohort of 255 patients (OEP001105), we characterized the immune and malignant epithelial landscapes associated with IM. We identified ANGPTL4-positive tumor-associated macrophages and hypoxia-associated malignant epithelial cells that were enriched in the IM group. Mechanistically, hypoxia induced the transcription factor CEBPB in macrophages, which directly activated ANGPTL4 transcription. Macrophage-derived ANGPTL4 subsequently engaged Integrin α5β1 on iCCA cells, activating the FAK/Src/GSK3β/β-catenin signaling cascade, promoting β-catenin nuclear translocation, and inducing epithelial-mesenchymal transition-associated remodeling. Functional assays and in vivo metastasis models demonstrated that ANGPTL4 enhanced iCCA cell migration, invasion, and liver metastasis, whereas ANGPTL4 blockade attenuated these effects. Clinical validation using ELISA and multiplex immunofluorescence further showed that elevated serum and tissue ANGPTL4 levels were associated with tumor burden and IM. Collectively, our study reveals a hypoxia-driven tumor microenvironmental communication axis between tumor-associated macrophages and malignant epithelial cells, highlighting ANGPTL4 as a potential non-invasive serum biomarker and therapeutic target for iCCA intrahepatic metastasis.
SLC27A5 deficiency-induced reduction in long-chain fatty acid uptake is a pro-tumorigenic metabolic adaptation and confers sensitivity to glutaminase inhibition in hepatocellular carcinoma.
He X, Zhao Z, Wei T … +13 more , Zheng L, Yang J, He X, Cheng Y, Zhan X, Li Z, Wu K, Roessler S, Jian Y, Fu C, Yan GR, Xu J, Zhang Q
Cancer Lett · 2026 Sep · PMID 42202975 · Publisher ↗
Hepatocellular carcinoma (HCC) exhibits diminished capacity for oxidative utilization of long-chain fatty acids (LCFAs). However, the strategic and mechanistic basis by which HCC cells enact metabolic reprogramming to ad...
Hepatocellular carcinoma (HCC) exhibits diminished capacity for oxidative utilization of long-chain fatty acids (LCFAs). However, the strategic and mechanistic basis by which HCC cells enact metabolic reprogramming to adapt to impaired LCFAs oxidation and sustain viability remains incompletely defined. Here we report that solute carrier family 27 member 5 (SLC27A5), the specific transporter for LCFAs, is broadly downregulated in HCC cells, resulting in reduced LCFAs uptake. In HCC cells with impaired LCFAs oxidation, diminished LCFAs import caused by SLC27A5 loss does not lead to energy deficiency, but instead prevents lipotoxicity derived from unutilized LCFAs, thereby supporting HCC cell growth. Impaired LCFAs oxidation suppresses peroxisome proliferator-activated receptor alpha (PPAR-α) signaling, which in turn represses SLC27A5 transcription, accounting for the widespread downregulation of SLC27A5 in HCC. Owing to reduced LCFAs uptake, HCC cells with low SLC27A5 rely on the glutamine reductive pathway for fatty acid biosynthesis to maintain total fatty acid levels, rendering these cells highly sensitive to glutaminase inhibition. In conclusion, we demonstrate that SLC27A5 downregulation represents a response to defective LCFAs oxidation in HCC, and reduced LCFAs uptake consequent to low SLC27A5 expression constitutes a survival adaptation that enables HCC to tolerate impaired LCFAs oxidation. Glutaminase inhibitors may serve as a precision therapeutic strategy for HCC characterized by low SLC27A5 expression.
Cannabidiol alleviates chemotherapy-induced cognitive decline and neuropathology.
Madan S, El-Khatib SM, Prathigudupu A … +7 more , Avalos HC, Ahmed F, Piomelli D, Chan A, Gupta K, Jung KM, Acharya MM
Cancer Lett · 2026 May · PMID 42202974 · Publisher ↗
Chemotherapy is frequently associated with long-term cognitive impairments in cancer survivors that negatively impact their quality of life. Effective mitigation strategies for cancer therapy-related cognitive impairment...
Chemotherapy is frequently associated with long-term cognitive impairments in cancer survivors that negatively impact their quality of life. Effective mitigation strategies for cancer therapy-related cognitive impairments (CRCI) are still underdeveloped. Our clinical studies on breast cancer patients treated with doxorubicin (Adriamycin®, ADR) and cyclophosphamide (CYP) found significant CRCI associated with neurodegenerative and neuroinflammatory signatures. Current preclinical and clinical studies highlight the potential of cannabidiol (CBD) for alleviating cognitive deficits in neurodegenerative conditions. For example, Epidiolex® is an FDA-approved 99% pure formulation of CBD for treating pediatric epilepsy. CBD, a non-psychoactive component of cannabis, is recognized for its neuroprotective and anti-inflammatory effects. This study, using a mouse model of adjuvant chemotherapy (ADR and CYP)-induced cognitive decline, tested the efficacy of oral administration of 99% pure CBD (20 mg/kg) in sesame oil. ADR + CYP-treated mice receiving CBD for one month showed significant neurocognitive improvements in learning and memory, executive function, and memory consolidation tasks often impaired in cancer survivors. CBD treatment also restored brain endocannabinoid (ECB) levels and reduced ECB-metabolizing enzymes in vivo. Notably, CBD mitigated chemotherapy-induced loss of neurogenesis, neuronal plasticity, synaptic density, and elevated gliosis. In summary, this data provides preclinical evidence for a translationally feasible approach to alleviate CRCI, an unmet medical need.
LINC01186-mediated deubiquitination of ACSL4 reprograms lipid metabolism to increase autophagy-mediated angiogenesis in colorectal cancer.
Li J, Luo Q, Xu C … +9 more , Ding J, Lu C, Zhan T, Chang L, Wang J, Wang J, Zhu J, Li J, Wang K
Cancer Lett · 2026 Sep · PMID 42190791 · Publisher ↗
Angiogenesis supports colorectal cancer (CRC) proliferation and metastasis, yet how lipid metabolic reprogramming intersects with angiogenesis signaling remains unclear. Here, we found that LINC01186 is upregulated in CR...
Angiogenesis supports colorectal cancer (CRC) proliferation and metastasis, yet how lipid metabolic reprogramming intersects with angiogenesis signaling remains unclear. Here, we found that LINC01186 is upregulated in CRC and correlates with advanced stage and poor prognosis. Mechanistically, LINC01186 functions as a molecular scaffold that concurrently interacts with the deubiquitinating enzyme USP4 and long-chain fatty acyl-CoA synthetase ACSL4, facilitating USP4-mediated deubiquitination of ACSL4. Elevated ACSL4 facilitates the accumulation of polyunsaturated fatty acids (PUFAs), namely arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid. Notably, elevated PUFA levels protect VEGFA from autophagy-lysosomal degradation by reducing autophagic flux, resulting in VEGFA overexpression and consequent promotion of angiogenesis. The absence of LINC01186 or ACSL4 impairs this signaling cascade, reduces PUFA levels, reactivates the autophagic degradation of VEGFA, and markedly obstructs the migration, invasion, and angiogenesis of CRC cells both in vitro and in vivo. Exogenous PUFA supplementation fully restores these abnormalities, which supports the essential involvement of lipid reprogramming in this mechanism. The LINC01186/ACSL4/VEGFA axis is essential in the formation and progression of CRC, with the overexpression of LINC01186 likely acting as a significant catalyst for excessive angiogenesis and metastatic advancement. Our findings highlight a unique lncRNA-mediated regulatory mechanism that connects deubiquitination, lipid metabolism, autophagy, and angiogenesis. Notably, although ferroptosis was not directly assessed in this study, the LINC01186/USP4/ACSL4 axis may have broader implications for ferroptosis research given that ACSL4 is a critical regulator of ferroptosis. Taken together, these results suggest that the LINC01186/USP4/ACSL4 axis represents a prospective therapeutic target for anti-angiogenic treatment in CRC.
SLC30A7 phosphorylation by ERK1 promotes esophageal squamous cell carcinoma tumorigenesis via activating MMP2/3/9-β-catenin signaling.
Yang L, Yao N, Zhou L … +10 more , Zhou R, Wang J, Yang R, Fan Y, Nie W, Liu K, Jiang W, Kim DJ, Dong Z, Li X
Cancer Lett · 2026 Sep · PMID 42190790 · Publisher ↗
Zinc ions (Zn) are crucial for cellular homeostasis, with their intracellular concentrations tightly regulated by multiple zinc transporters located at the plasma and organelle membranes. Zinc dysregulation has been impl...
Zinc ions (Zn) are crucial for cellular homeostasis, with their intracellular concentrations tightly regulated by multiple zinc transporters located at the plasma and organelle membranes. Zinc dysregulation has been implicated in esophageal squamous cell carcinoma (ESCC), yet the oncogenic roles of zinc transporters remain poorly understood. We herein identify SLC30A7 as a zinc transporter markedly elevated in ESCC and associated with poor prognosis. Genetic deletion of Slc30a7 significantly suppressed 4NQO-induced esophageal tumorigenesis, whereas SLC30A7 knockdown inhibited ESCC cell proliferation, migration, and tumor progression. Mechanistically, ERK1 specifically binds SLC30A7 and phosphorylates SLC30A7 at T297 site, driving the redistribution of zinc (Zn) from the cytosol into the Golgi lumen. SLC30A7 cooperates with the zinc metallochaperone ZNG1 to mobilize Golgi-resident zinc toward matrix metalloproteinases MMP2/3/9 activation, leading to E-cadherin degradation, β-catenin nuclear translocation, and MYC transcription. In ESCC PDX models, a tumor-targeted biomimetic ERK inhibitor nanoplatform (Q3ME@PBA-NPs) significantly restrained tumor growth and disrupted the ERK1-SLC30A7-MMP2/3/9-β-catenin-c-Myc axis. These findings reveal a previously unrecognized zinc-dependent oncogenic pathway in ESCC and highlight SLC30A7 as a valuable therapeutic target in cancer.
From linker stability to linker fitness: redefining ADC design for clinical translation.
Ma W, Klacking E, Jamieson C
Cancer Lett · 2026 May · PMID 42190789 · Publisher ↗
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Exosome mediated crosstalk in gastrointestinal cancers progression: special focus on Integrin β3 as a cargo.
Nagaraju GP, Sarvesh S, El-Rayes BF
Cancer Lett · 2026 Aug · PMID 42184922 · Publisher ↗
Intercellular communication within the tumor microenvironment (TME) is highly active in gastrointestinal (GI) cancers, and exosomes have an important function in tumor development, progression, metastasis, angiogenesis,...
Intercellular communication within the tumor microenvironment (TME) is highly active in gastrointestinal (GI) cancers, and exosomes have an important function in tumor development, progression, metastasis, angiogenesis, and drug resistance. Exosomes secreted by tumor cells actively remodel their local environment by delivering oncogenic proteins, genetic material, and integrins, contributing to processes such as invasion, immune escape, and metastatic niche formation. Cancer-associated fibroblasts (CAFs) are a main source of exosomes in the stroma, and their presence boosts tumor progression by orchestrating changes in the extracellular matrix composition, metabolism, and epithelial to mesenchymal transition. Similarly, exosomes produced by endothelial cells facilitate angiogenesis and increase vascular permeability, providing a mechanism for tumor spread. One of the key factors recently discovered in exosomes is the integrin β3, which plays a major role in organotropic metastasis, cell adhesion, migration, and activation of signaling pathways in GI cancers. In this review, the biological roles of exosomes isolated from tumors, CAFs, and endothelial cells have been highlighted, especially with reference to the functional significance of integrin β3 in GI cancers. This review also provides insight into the application of integrin β3 in exosomes as a biomarker for early detection, diagnosis, and treatment. The knowledge gained through exosome-based signaling could lead to new approaches for interfering with TME-associated tumor progression.
RAC1 signaling in polyploid giant cancer cells: Implications for tumorigenesis and therapy resistance.
Sthanam LK, Mendez PM, McBeath E … +3 more , Cruz L, Bagheri-Yarmand R, Hofmann MC
Cancer Lett · 2026 May · PMID 42184921 · Publisher ↗
Polyploid giant cancer cells (PGCCs) are a subpopulation of tumor cells known for driving tumor recurrence, metastasis, and therapeutic resistance. PGCCs arise mainly in response to cellular stress induced by cancer ther...
Polyploid giant cancer cells (PGCCs) are a subpopulation of tumor cells known for driving tumor recurrence, metastasis, and therapeutic resistance. PGCCs arise mainly in response to cellular stress induced by cancer therapies and adverse microenvironmental conditions. We have recently demonstrated that a RAC1 mutation (RAC1 P34R) can induce the formation of PGCCs in aggressive thyroid cancer cells from a patient undergoing dabrafenib treatment, leading to resistance to therapy. RAC1 is a critical regulator and integrator molecule that mediates multiple cellular processes ranging from stress adaptation, metabolic regulation, cytoskeletal dynamics, motility, and cytokinesis. Importantly, RAC1's functions are highly context-dependent, varying across a cell's life cycle stages in response to dynamic biomechanical factors from the tumor microenvironment. This complexity underscores the need for precision targeting strategies that account for RAC1's dynamic roles. Therapeutic approaches aimed at modulating RAC1 must be tailored to the specific cellular context and PGCC state to effectively disrupt the mechanisms underlying tumor progression. By targeting RAC1's integrative functions, researchers may unlock new avenues for preventing PGCC-mediated recurrence and metastasis, offering a promising strategy to improve long-term outcomes in cancer treatment. This review outlines the diverse functions of RAC1 that may contribute to both the formation and sustained maintenance of PGCCs across various tumor types.
Pharmacological induction of mitochondria-lysosome hyper-tethering elicits synthetic lethality in glioblastoma.
Su D, Huang Y, Hong B … +9 more , Cui X, Zhao J, Zhan Q, Yi K, Ding Y, Xu H, Wang Q, Guo H, Kang C
Cancer Lett · 2026 Aug · PMID 42184920 · Publisher ↗
The clinical translation of synthetic lethality between cytoplasmic phospholipase A2 (cPLA2) and dipeptidyl peptidase 4 (DPP4) in glioblastoma (GBM) has been hindered by the absence of clinically applicable cPLA2 inhibit...
The clinical translation of synthetic lethality between cytoplasmic phospholipase A2 (cPLA2) and dipeptidyl peptidase 4 (DPP4) in glioblastoma (GBM) has been hindered by the absence of clinically applicable cPLA2 inhibitors. In this study, we demonstrate that quinacrine, a clinically available drug with cPLA2 inhibitory activity, synergizes with the DPP4 inhibitor linagliptin to exert potent anti-tumour effects. This combination synergistically depleted mitochondrial proteins, and inhibited GBM growth, significantly prolonging survival compared with temozolomide. Mechanistically, quinacrine promoted p62-dependent autophagic degradation of both cPLA2 and the mitochondrial fission protein FIS1, while linagliptin disrupted a DPP4-EGFR positive feedback loop, impairing EGFR-mediated phosphorylation of RAB7 at Ser72 and thereby stabilizing GTP-bound RAB7. These parallel inhibitions converged to enhance the frequency and duration of mitochondria-lysosome contacts, leading to massive mitochondrial degradation and bioenergetic collapse through a process termed mitochondria-lysosome hyper-tethering (MLHT). Furthermore, we established a composite transcriptional signature (DPP4-CPLA2-FIS1, DCF score) that reflects axis activity and enables metabolic stratification and therapeutic guidance for GBM. Our work not only presents a clinically feasible strategy for GBM treatment but also redefines the synthetic lethal interaction by shifting the target pair from cPLA2-DPP4 to the effector pair FIS1-RAB7, establishing hyper-activated mitochondria-lysosome tethering as a druggable anti-tumour mechanism.
Desmoplasia and therapeutic resistance in pancreatic ductal adenocarcinoma.
Ghanwatkar Y, Ramanathan R, Mahato RI
Cancer Lett · 2026 Aug · PMID 42184919 · Publisher ↗
Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal solid malignancies, and its therapeutic failure reflects both aggressive tumor-cell biology and the highly restrictive tumor microenvironment (TME). A...
Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal solid malignancies, and its therapeutic failure reflects both aggressive tumor-cell biology and the highly restrictive tumor microenvironment (TME). A defining hallmark of PDAC is desmoplasia, an extensive, extracellular matrix (ECM)-rich fibroinflammatory reaction that frequently exceeds the tumor cell compartment itself. Evidence from genetically engineered mouse models and human specimens identifies pancreatic stellate cells (PSCs) as the dominant architects of this stroma. Upon activation, PSCs differentiate into matrix-producing fibroblasts that drive collagen and hyaluronan (HA) accumulation, tissue stiffening, and vascular compression. ECM remodeling elevates interstitial pressure, collapses perfused vessels, and establishes profound hypoxia, which in turn reinforces fibroblast activation and matrix deposition through feed-forward signaling loops. These hypoxic, high-stress conditions severely restrict the delivery of cytotoxic agents, biologics, and nanomedicines, while simultaneously activating mechanotransduction pathways that enhance tumor cell survival under therapy. Clinical attempts to ablate stromal components validated the barrier function of desmoplasia but also revealed its tumor-restraining roles, exposing the limitations of indiscriminate depletion. This review synthesizes PSC-driven stromal initiation, matrix biomechanics, spatial zonation, and formulation-aware delivery into a single framework to explain why stromal targeting has repeatedly failed clinically and which normalization strategies are most likely to improve therapeutically effective exposure in PDAC.
Repurposing the Neurokinin-1 receptor antagonist Aprepitant to eradicate relapsed/refractory acute lymphoblastic leukemia via mitochondria-driven necroptosis.
Shao G, Pan H, Zhu J … +11 more , Zhuo N, Cheng X, Wu H, Xiao R, Hong X, Li J, Ma J, Tong X, Wang H, Wang X, Fu C
Cancer Lett · 2026 May · PMID 42184918 · Publisher ↗
The prognosis for relapsed/refractory acute lymphoblastic leukemia (R/R ALL) remains dismal due to intrinsic and acquired chemoresistance, highlighting an urgent need for novel therapeutic strategies. The neurokinin-1 re...
The prognosis for relapsed/refractory acute lymphoblastic leukemia (R/R ALL) remains dismal due to intrinsic and acquired chemoresistance, highlighting an urgent need for novel therapeutic strategies. The neurokinin-1 receptor (NK-1R) represents an emerging oncological target, yet its role and therapeutic potential in ALL are incompletely understood. Here, we identify the NK-1R as a robust therapeutic target that is significantly overexpressed in both primary and R/R ALL. The FDA-approved NK-1R antagonist Aprepitant potently inhibited the proliferation of ALL cells and overcame resistance to chemotherapeutic drugs in both patient-derived samples and doxorubicin-resistant cell lines. Mechanistically, Aprepitant triggered a novel mitochondria-driven necroptotic pathway, distinct from the apoptosis induced by NK-1R blockade in other cancers we previously reported [5,6]. This pathway is initiated by endoplasmic reticulum (ER) calcium release and ER stress, leading to mitochondrial calcium overload, reactive oxygen species (ROS) burst, and subsequent mitochondrial fission, which ultimately activates the phosphorylation of the core necroptotic effectors RIP1, RIP3, and MLKL. Pharmacological inhibition or genetic knockdown of key regulators of necroptosis, ER stress, or mitochondrial ROS significantly attenuated Aprepitant-induced cell death. Importantly, Aprepitant exhibited significant in vivo anti-leukemic efficacy in a xenograft mouse model. Our findings not only elucidate a unique, mitochondria-mediated necroptotic mechanism engaged by NK-1R inhibition but also provide a compelling rationale for the immediate clinical repurposing of Aprepitant as a targeted therapy for R/R ALL.
NAB2::STAT6 fusion proteins drive nuclear condensate formation and transcriptional reprogramming in solitary fibrous tumors.
Li Y, Mondaza-Hernandez JL, Pulivendala G … +13 more , Elsenduny F, Beckedorff F, Lavezzo GM, Azad FV, Zhou Z, Warren J, Trevino PI, Meyer CA, Lombard DB, Martin-Broto J, Moura DS, Hayenga HN, Bleris L
Cancer Lett · 2026 Aug · PMID 42176797 · Publisher ↗
Solitary fibrous tumor (SFT) is a rare and aggressive sarcoma driven by NAB2::STAT6 gene fusions, yet effective targeted therapies remain unavailable. Here, we report that the NAB2ex4::STAT6ex2 fusion variant forms nucle...
Solitary fibrous tumor (SFT) is a rare and aggressive sarcoma driven by NAB2::STAT6 gene fusions, yet effective targeted therapies remain unavailable. Here, we report that the NAB2ex4::STAT6ex2 fusion variant forms nuclear condensates via liquid-liquid phase separation (LLPS) in engineered fibroblast models and primary SFT cells. These condensates co-localize with BRD4S and EGR1, key transcriptional regulators, and are functionally active, driving widespread transcriptional reprogramming. Treatment with Mithramycin A, a compound that disrupts EGR1-DNA interactions, dissolves NAB2::STAT6 condensates and reverses their aberrant gene expression and chromatin binding signatures. Our findings uncover a previously unrecognized role for NAB2::STAT6 in condensate-mediated oncogenic signaling and provide a mechanistic rationale for condensate-targeted therapy in SFT.
Nanoplasmid PSMA DNA vaccine primes antitumor immunity and enhances response to PD-1 blockade against prostate cancer.
Maza PAMA, Flores L, Cyril-Ramirez D … +3 more , Neeli P, Ni H, Li Y
Cancer Lett · 2026 Sep · PMID 42176796 · Publisher ↗
Prostate cancer (PCa) remains a leading cause of cancer-related mortality among men particularly in metastatic castration-resistant disease, which is refractory to immune checkpoint blockade. Prostate-specific membrane a...
Prostate cancer (PCa) remains a leading cause of cancer-related mortality among men particularly in metastatic castration-resistant disease, which is refractory to immune checkpoint blockade. Prostate-specific membrane antigen (PSMA) is highly overexpressed and correlated with PCa aggressiveness and invasiveness. In this study, we evaluated the prophylactic and therapeutic potential of a next generation Nanoplasmid-based DNA vaccine encoding human PSMA (N-hPSMA). We demonstrated that Nanoplasmid resulted in faster, higher, and more sustained transgene expression compared with a conventional plasmid vector, which led to a significant increase in hPSMA-specific cellular and humoral immune response. Prophylactic vaccination conferred tumor eradication and prevented lung metastasis. N-hPSMA vaccination increased systemic immune activation with abated regulatory T cell population and augmentation of effector-memory CD8 T cells. In the therapeutic setting, N-hPSMA slowed tumor growth and potentiated PD-1 blockade, resulting in enhanced tumor regression and survival, while increasing activation of myeloid antigen presenting cells. In a humanized orthotopic PCa model, N-hPSMA vaccination plus PD-1 blockade significantly increased functional human CD8 T cells and suppressed the growth of human PCa LNCaP tumors. These findings established N-hPSMA as a preclinical proof-of-concept DNA vaccine that enhances antitumor immunity and sensitizes PCa to immune checkpoint blockade.
Tamoxifen enhances radiation efficacy by promoting M1 polarization of tumor associated macrophages via JNK/c-JUN pathway.
Ma S, Chen M, Sun X … +12 more , Wei B, Sun F, Xie X, Huang Y, Liu Z, Xiao R, Wei L, Wang F, Xu Y, Yu J, Chen D, Wu M
Cancer Lett · 2026 Sep · PMID 42176795 · Publisher ↗
Tamoxifen has been commonly used in endocrinotherapy for estrogen receptor (ER)-positive breast cancer. In recent years, the immunomodulatory effects of high-dose tamoxifen have been discovered. The immunosuppressive tum...
Tamoxifen has been commonly used in endocrinotherapy for estrogen receptor (ER)-positive breast cancer. In recent years, the immunomodulatory effects of high-dose tamoxifen have been discovered. The immunosuppressive tumor microenvironment (TME), however, remains a major obstacle to the efficacy of radiotherapy. Whether high-dose tamoxifen can reprogram TME to synergistically enhance radiation efficacy is still ambiguous. Here, we have found high-dose tamoxifen could dramatically enhance radiation-induced antitumor effects without significant side effects in immunocompetent mice. Flow cytometry and multiplex immunofluorescence experiments revealed that radiation combined with tamoxifen resulted in significant enrichment of effector CD8 T cells and M1 tumor associated macrophages (TAMs). Depletion of TAMs and CD8 T cells impaired the synergistic antitumor effects mediated by combination treatment of radiation and tamoxifen. Furthermore, spatial proximity analysis demonstrated a dramatically reduced nearest-neighbor distance between CD8 T cells and M1-like TAMs in the combination group, indicating enhanced cellular interaction within the TME. In vitro experiments demonstrated that tamoxifen directly acted on TAMs, rather than CD8 T cells, to promote M1 polarization and subsequently enhanced the activation and effector function of CD8 T cells, regardless of ER expression in tumor cells and macrophages. Mechanistically, RNA-sequencing and experimental validation uncovered that tamoxifen and tumor cell-derived TNF-α and IL-1β after irradiation synergistically activated the JNK/c-JUN pathway and promoted M1 polarization of TAMs. In conclusion, our study revealed the immunomodulatory effects of high-dose tamoxifen in the context of radiation and provided preclinical evidence for combination therapy of high-dose tamoxifen and radiotherapy in both ER-positive and ER-negative cancers.
Biomarker-Guided Strategies for Tumor Vasculature: From Imaging Advances to Novel Therapeutic Interventions.
Purcell C, Ryspayeva D, Gopal J … +8 more , Schmidt A, Vaughn-Beaucaire P, Su AY, Lawler SE, MacDonald WJ, Pinho-Schwerrman M, Seyhan AA, El-Deiry WS
Cancer Lett · 2026 May · PMID 42176794 · Publisher ↗
The tumor vasculature is a dynamic and heterogeneous component of the tumor microenvironment (TME) that influences tumor progression, immune infiltration, metastatic spread, and therapeutic response. This review explores...
The tumor vasculature is a dynamic and heterogeneous component of the tumor microenvironment (TME) that influences tumor progression, immune infiltration, metastatic spread, and therapeutic response. This review explores the factors that contribute to the unique vascular characteristics of the TME, highlighting the potential for molecular and imaging biomarkers to predict treatment outcomes. We discuss structural and functional abnormalities of tumor vessels, including altered architecture, permeability, interstitial pressure, endothelial phenotype, and impaired drug delivery. We also examine angiogenic signaling through hypoxia-inducible factor 1 (HIF1) and vascular endothelial growth factor (VEGF), while highlighting non-angiogenic mechanisms such as vessel co-option. The review then turns to the current clinical landscape of angiogenesis, assessing the success and limitations of current therapies, emerging treatment strategies, biomarkers associated with angiogenesis, and AI-assisted prognostication. The establishment and clinical utilization of angiogenesis and tumor vasculature biomarkers is critical for disease diagnosis, prognosis, and the development of targeted therapies. This review aims to inform future innovation in personalizing oncological therapies that harness insights into the behavior of the tumor vasculature, enhancing the precision and effectiveness of cancer treatment.
Kinase-independent signaling by PIM1 promotes drug resistance by increasing mitophagy and reducing oxidative stress.
Liou H, Chauhan SS, Flores CE … +7 more , Kinkade R, Ressel MR, Cress AE, Langlais PR, Sutar YB, Date AA, Warfel NA
Cancer Lett · 2026 Aug · PMID 42176793 · Publisher ↗
PIM kinases are overexpressed in castration resistant prostate cancer (CRPC) and many small molecule PIM kinase inhibitors (smPIM inhibitors) have been designed to block the catalytic activity of PIM. However, smPIM inhi...
PIM kinases are overexpressed in castration resistant prostate cancer (CRPC) and many small molecule PIM kinase inhibitors (smPIM inhibitors) have been designed to block the catalytic activity of PIM. However, smPIM inhibitors have shown limited efficacy in solid tumors. Notably, all these inhibitors share the common property that they increase total PIM protein levels, which limits their efficacy because PIM1 has kinase-independent pro-survival effects. Here, we identify high mobility box group 1 (HMGB1) as a novel PIM1 binding partner. Stabilization of PIM1 by smPIM inhibitors increases the cytosolic accumulation of HMGB1, which leads to activation of mitophagy and suppresses oxidative-stress induced cell death. Knockdown of PIM1/2/3 and/or HMGB1 sensitizes cancer cells to smPIM inhibitors. In contrast, treatment with a PIM PROTAC (PIMTAC) that we developed overcomes the kinase-independent pro-survival effects of PIM1 and is more effective than smPIM inhibitors in vitro and in vivo. These results uncover a mechanism of resistance that has limited the success of smPIM inhibitors and provides compelling evidence that targeted degradation of PIM is needed to realize its potential as an anti-cancer target.
EGFR S442 ectodomain mutation confers cetuximab resistance that can be overcome by ERBB2 blockade with trastuzumab-deruxtecan.
Harmych SJ, Joshi N, Tanaka H … +29 more , Bogatcheva G, Ramirez MA, Graves-Deal R, Tydings CW, Elia MT, Mueller HRL, Silvestri IM, Ti Ning K, Wahoski CC, Sievers CK, Higginbotham JN, Irudayam MJ, Revetta FL, Zhao Z, Franklin JL, Yilma B, O'Grady TM, Fragkogianni S, Ciampricotti M, Washington MK, Guo X, Lovly CM, Walker AS, Meiler J, Mudumbi KC, Liu Q, Coffey RJ, Rosenthal E, Singh B
Cancer Lett · 2026 Aug · PMID 42176792 · Publisher ↗
Epidermal growth factor receptor (EGFR) is an oncogenic driver in multiple cancers and a therapeutic target of tyrosine kinase inhibitors and neutralizing monoclonal antibodies. However, resistance to EGFR-targeted thera...
Epidermal growth factor receptor (EGFR) is an oncogenic driver in multiple cancers and a therapeutic target of tyrosine kinase inhibitors and neutralizing monoclonal antibodies. However, resistance to EGFR-targeted therapies, particularly the anti-EGFR antibody cetuximab, remains a clinical challenge in colorectal (CRC) and head and neck (HNSCC) cancers. Cetuximab exerts its antitumor activity by blocking ligand-dependent EGFR signaling and by engaging immune effector mechanisms. To investigate cetuximab resistance mechanisms, we cultured the cetuximab-sensitive CRC cell line DiFi in 3D with cetuximab, generating the cetuximab-resistant derivative (DiFi-CR). Genomic and transcriptomic profiling revealed that DiFi-CR cells harbor a mutation of the S442 residue within the EGFR ectodomain. Patient samples revealed recurrent EGFR S442 mutations following anti-EGFR therapy, suggesting S442 as a potential resistance hotspot. For mechanistic analyses, we reconstituted the EGFR S442I mutation, using a doxycycline-inducible system, and showed that it was necessary and sufficient to induce cetuximab resistance in CRC and HNSCC cells using in vitro cultures and in vivo mouse experiments. In silico studies, live-cell binding assays, and antibody enrichment in nude mice xenografts revealed that the S442I mutation leads to weaker EGFR-cetuximab binding. Weaker cetuximab binding was also predicted in silico for other S442 patient mutations. We found that mutant EGFR-driven resistance could be overcome by targeting the EGFR family member, ERBB2, with trastuzumab-deruxtecan. This combinatorial response required a physical interaction between EGFR and ERBB2, determined by co-immunoprecipitation. Our study supports EGFR S442 mutations as cetuximab resistance drivers and highlights co-targeting ERBB2 as a therapeutic strategy to restore anti-EGFR efficacy.
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