Yang B, Liu X, Wei J
… +13 more, Xu L, Zhang J, Fan M, Hou Y, Zhang F, Chen Y, Liu W, Li Y, Liu Z, Chen K, Tian X, Yang Y, Ma Y
Cancer Lett
· 2026 Mar · PMID 41887395
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The stratification of pancreatic ductal adenocarcinoma (PDAC) remains challenging due to the limitations of current staging systems and the ineffectiveness of the serum biomarker CA19-9 in a significant patient subgroup....The stratification of pancreatic ductal adenocarcinoma (PDAC) remains challenging due to the limitations of current staging systems and the ineffectiveness of the serum biomarker CA19-9 in a significant patient subgroup. We developed and validated a deep learning-based pathomic signature (PCPS) using routinely acquired haematoxylin and eosin (H&E)-stained whole-slide images from 252 patients at our institution and an external cohort of 183 patients from TCGA. PCPS robustly predicted overall and recurrence-free survival (C-indices: 0.64 and 0.61 internally, 0.62 and 0.61 externally). Crucially, it effectively stratified CA19-9-negative patients into high- and low-risk groups with significantly distinct outcomes (OS: HR = 9.26, P < 0.001; RFS: HR = 5.02, P < 0.001). Biological interpretation linked the high-risk score to an immunosuppressive microenvironment and a basal-like epithelial cell state. Our study establishes PCPS as a powerful, biologically interpretable, and clinically actionable prognostic biomarker that could guide personalized therapy for PDAC, particularly for patients lacking conventional serological markers.
Yang C, Mei R, Liu J
… +12 more, Shen X, Zhang H, Li Q, Gan D, Shi J, Yang R, Zhao Y, Lu Y, Li H, Wang K, Li J, Su H
Cancer Lett
· 2026 Jun · PMID 41887394
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Suboptimal glycemic control facilitates tumor immune evasion, severely impairing the prognosis of patients with cancer. Tumor cell softness, a critical biomechanical property, is closely associated with cell proliferatio...Suboptimal glycemic control facilitates tumor immune evasion, severely impairing the prognosis of patients with cancer. Tumor cell softness, a critical biomechanical property, is closely associated with cell proliferation, migration, and immune cell interactions, thereby regulating tumor progression. However, whether blood glucose induces immune evasion by modulating tumor cell hardness-defined as a "physical property immune checkpoint"-and its underlying mechanisms remain unclear. This study demonstrates that elevated glucose concentrations in culture systems progressively soften tumor cells, reducing the cytotoxicity of CD8 T cells. Specifically, glucose increases cytoplasmic and plasma membrane cholesterol levels in tumor cells, reducing cellular hardness. Mechanistically, hyperglycemia disrupts DNA methylation in tumor cells: dysregulated expression of DNA methyltransferase DNMT3A and demethylase TET2 enhances methylation of the cholesterol efflux gene ABCA1 promoter, downregulating ABCA1. Impaired ABCA1 hinders cholesterol efflux, causing intracellular accumulation, increasing plasma membrane cholesterol, softening cells, and weakening T-cell cytotoxicity. Additionally, BCL11B binds the ABCA1 promoter, recruiting DNMT3A and TET2 to regulate methylation. In conclusion, this study identifies glucose-mediated modulation of the tumor cell membrane-force axis in immune evasion, clarifies the links between hyperglycemia-induced DNA methylation dysregulation, aberrant cholesterol accumulation and the cell hardness, contributing to the poor prognosis of cancer patients with suboptimal glycemic control from a biomechanical perspective.
Yan H, Mao AW, Li D
… +18 more, Fu G, Pérez-Baena MJ, Jiménez-Navas A, Wang D, Hong R, Cai W, Pérez-Losada J, Jen KY, Wang S, Peng S, Barcellos-Hoff MH, Shen H, Lin N, Mao JH, Fu Y, Iczkowski KA, Gulati S, Chang H
Cancer Lett
· 2026 Jun · PMID 41887393
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It is imperative to identify patients with prostate cancer (PCa) who will not benefit from androgen receptor signaling inhibitors and to improve their clinical outcomes. Using artificial intelligence (AI), in this multic...It is imperative to identify patients with prostate cancer (PCa) who will not benefit from androgen receptor signaling inhibitors and to improve their clinical outcomes. Using artificial intelligence (AI), in this multicenter cohort study of 623 PCa patients, we identified 13 cellular morphometric biomarkers (CMBs), as a New Approach Methodology (NAM), from whole slide images of needle biopsies in clinical trial specimens (NCT02430480, n = 37) that accurately predicted response to neoadjuvant androgen deprivation therapy (NADT) plus enzalutamide (AUC: 0.981, 95% CI [0.979, 0.983]). Importantly, the 13-CMB model stratified PCa patients into responders and non-responders after NADT across two independent hospital cohorts. In one cohort (n = 122), the model identified groups with significantly different pathologic complete response (pCR) (p = 0.0005) and biochemical recurrence-free survival (BCRFS) (p = 0.024). In the second cohort (n = 60), the model similarly distinguished patients with significantly different BCRFS (p = 0.031). The 13-CMB model also stratified PCa patients in the TCGA-PRAD cohort (n = 396) with distinct progression-free survival (p = 0.0017). Importantly, across hospital cohorts and the TCGA-PRAD cohort, the 13-CMB model demonstrated significant and independent clinical value after adjustment for established clinical factors and commonly used genomic biomarkers, including Decipher and Oncotype DX. Furthermore, CMBs accurately predicted the molecular differences between stratified patient groups and the potential benefit from mTOR inhibitors in non-responders, which were validated through IHC staining and patient-derived organoids (n = 8), respectively. Overall, our AI-powered CMB model, relying only on routine needle biopsy specimens, could potentially serve as a robust solution for precision management of PCa patients.
Wang H, Shen T, Yang S
… +17 more, Zhou X, Cao P, Yu H, He K, Fu M, Yu H, Liu X, Zhou T, Wang J, Huang M, Qian X, Wang X, Wang Q, Liu L, Fan Z, Zhang Y, Lin F
Cancer Lett
· 2026 Jun · PMID 41887392
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Colorectal cancer (CRC) is the most prevalent digestive system malignancy worldwide. The development of targeted therapeutics specifically effective for CRC is currently in dire need. Preclinical studies showed that CDK4...Colorectal cancer (CRC) is the most prevalent digestive system malignancy worldwide. The development of targeted therapeutics specifically effective for CRC is currently in dire need. Preclinical studies showed that CDK4/6 inhibitor palbociclib suppressed the growth of CRC, but whether this effect is durable is unclear. In this study, we aimed to evaluate the roles of palbociclib-induced senescence and find a new strategy to maximize its effectiveness in CRC treatment. Animal and cellular experiments revealed that palbociclib-induced senescence and the senescence-associated secretory phenotype (SASP) caused drug resistance, anti-apoptosis, PD-L1 upregulation and inhibition of CD8 T cells' function. Using CRISPR/Cas9 screening, we identified MCL1 as a senolytic target to eliminate palbociclib-induced senescent CRC cells in the presence of palbociclib. Mechanically, palbociclib-induced senescent cells upregulated ZHX2 and its transcriptional target MCL1, rendered their resistance to apoptosis and T cell-mediated cytotoxicity, whereases combining palbociclib with MCL1 inhibitor markedly induced apoptosis in senescent cells by activating both extrinsic and intrinsic apoptotic pathways. Lastly, we proposed a seno-therapy consisting of a palbociclib pre-treatment plus a combination treatment of palbociclib and MCL1 inhibitor and found it effectively inhibited tumor growth and improved the survival of CRC xenografted mice. Besides its senolytic effect, seno-therapy also reduced PD-L1-positive cells and enhancing the cytotoxic functions of CD8 T cells. In conclusion, co-targeting CDK4/6 and MCL1 efficiently eliminates palbociclib-induced senescent CRC cells and offers a promising CDK4/6 inhibitor-based strategy for CRC treatment, ensuring prolonged tumor suppression and reducing the risk of progression or recurrence.
El-Gazzar A, Aschenbrenner B, Forsthuber A
… +22 more, Kramer M, Kargarpour Z, Metekol S, John L, Papaporfyriou A, Bereš M, Trouvilliez S, Homolya M, Döme B, Megyesfalvi Z, Horvath L, Lang C, Hoda MA, Zeillinger R, Obermayr E, Geleff S, Frommlet F, Lichtenberger BM, Gompelmann D, Casanova E, Moll HP, Idzko M
Cancer Lett
· 2026 Jun · PMID 41887391
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The enrichment of immunosuppressive M2 macrophages, combined with diminished CD8 T cell infiltration, represents a key mechanism driving tumor progression and limiting immunotherapy efficacy in non-small cell lung cancer...The enrichment of immunosuppressive M2 macrophages, combined with diminished CD8 T cell infiltration, represents a key mechanism driving tumor progression and limiting immunotherapy efficacy in non-small cell lung cancer (NSCLC). Here, we provide evidence that the purinergic P2Y2 receptor (P2RY2) is a key regulator of M2 macrophage enrichment and contributes to the exclusion of CD8 T cells from the tumor microenvironment (TME). P2RY2 expression is significantly elevated in human NSCLC compared to non-malignant tissues and M2-like macrophages expressing P2RY2 are more prevalent in tumors with an advanced TNM (Tumor, Node, Metastasis) stage. Elevated P2RY2 mRNA levels are significantly associated with poorer overall survival in a NSCLC patients. Furthermore, we selectively inhibited P2RY2 in syngeneic or autochthonous mouse models of NSCLC driven by Kras or Egfr mutations. This resulted in a significant reduction of M2-like macrophages, enhanced CD8 T cell migration and tumor infiltration and a marked decrease in tumor burden. Similar results were evident following the genetic deletion of P2ry2, validating the impact on the TME. Importantly, macrophages are the predominant P2RY2-expressing cells within the TME. Moreover, tumor-educated macrophages (TEMs) isolated from P2ry2 tumor-bearing mice exhibited reduced proliferation compared with wild-type macrophages when co-cultured with LLC1 cells, revealing a potential mechanism underlying P2RY2-mediated pro-tumorigenic activity. Our study underscores the clinical significance of P2RY2 in NSCLC and provides evidence of its pivotal role in the regulation of M2 macrophage enrichment and the exclusion of CD8 T cells from the TME. Targeting P2RY2 may offer a novel immunotherapeutic intervention for NSCLC.
Cheng M, Pang Y, Wang R
… +11 more, Chen X, Zhang C, Yang Y, Ji T, Wu Y, Wang J, Xu S, Wang Z, Liu M, Zhang J, Zhong C
Cancer Lett
· 2026 Jul · PMID 41881336
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Glioblastoma (GBM) poses a formidable challenge in the field of oncology because of its pronounced resistance to traditional therapeutic approaches. N6-methyladenosine (mA) modification is a prevalent posttranscriptional...Glioblastoma (GBM) poses a formidable challenge in the field of oncology because of its pronounced resistance to traditional therapeutic approaches. N6-methyladenosine (mA) modification is a prevalent posttranscriptional modification that significantly influences cellular processes by modulating gene expression. However, the role of mA in the regulation of the DNA damage response (DDR) in GBM cells remains unclear. Through integrated bioinformatics and functional studies, we identified the mA reader YTHDF3 as a central regulator of the DDR in GBM, and the elevated expression levels of YTHDF3 were correlated with unfavorable clinical outcomes in GBM patients. Human GBM cell lines and patient-derived GBM cells (PDC) models were used to explore the biological function of YTHDF3. Following treatment with temozolomide (TMZ), the level of mA modification was increased, facilitating YTHDF3-mediated DNA damage repair. The knockdown of METTL3 resulted in a reduction in functional mA modification and suppressed the expression of DDR core factors, which are mediated by YTHDF3. Mechanistically, YTHDF3 recognizes the mA binding site of DNA damage response genes (BRCA1, RAD51, RIF1 and 53BP1) and promotes their translation through mA methylation, thereby initiating homologous recombination (HR) and nonhomologous end joining (NHEJ) repair to resist endogenous and exogenous DNA damage. Consequently, our study elucidates the crucial role of YTHDF3 in GBM and provides valuable insights into its significance in the DNA damage response and chemoresistance.
Yang L, Yang H, Zhao M
… +10 more, Wen Y, Wu L, Chen Q, Cao F, Zhao Y, Ye D, Yuan M, Yu J, Sun X, Xing L
Cancer Lett
· 2026 Jun · PMID 41881335
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To investigate the mechanisms of early brain metastasis in non-small cell lung cancer (NSCLC) using spatial multi-omics technology, develop predictive models, and identify potential therapeutic targets. A retrospective a...To investigate the mechanisms of early brain metastasis in non-small cell lung cancer (NSCLC) using spatial multi-omics technology, develop predictive models, and identify potential therapeutic targets. A retrospective analysis was conducted on paraffin samples from 53 NSCLC patients (stages I-IV), including normal lung tissue (NL), primary tumors with/without brain metastasis (PT/PT), brain metastases (BrM), and normal brain tissue. Integrated single-nucleus RNA sequencing, GeoMx DSP, and CosMx SMI. Augur, pseudo-time, and space communication analysis identified key cells and molecules. ROC and survival analysis evaluated predictive performance. Potential preventive targets screened from the Therapeutic Target Database. snRNA-seq revealed that IGHG1 malignant epithelial cell (MEC) represent the terminal differentiation state of PT epithelium, showing significant enrichment in EMT pathways. These cells uniquely responded to biological perturbations (NL→PT vs NL→PT, 0.596 vs 0.000, P = 0.002). Spatial transcriptomics further indicated that IGHG1 MEC predominantly localized at the invasive front of PT, co-localizing with myofibroblastic cancer-associated fibroblast (myCAF; r = 0.900). Multi-omics demonstrated bidirectional interactions between IGHG1 MEC and myCAF at PT margins via MIF-CD74/APP-CD74 axes, which were also validated both clinically and in vitro. High CD74 at margins was an independent predictor of brain metastasis (AUC = 0.776; HR = 5.495), linked to shorter brain metastasis-free survival (37 vs 60 months, P < 0.0001). In vivo studies confirmed that the candidate drugs targeting CD74, doxorubicin and milatuzumab, have a tendency to inhibit EMT. IGHG1 MEC collaborate with myCAF to shape a pro-metastatic microenvironment, with the MIF-CD74/APP-CD74 interaction network serving as a driver of NSCLC brain metastasis. CD74-targeting therapies show promising clinical potential.
Cancer Lett
· 2026 Jun · PMID 41871801
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Skin cancers, including melanoma, cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC), present a fundamental paradox: high tumor immunogenicity coexists with profound immune evasion, driven by oncog...Skin cancers, including melanoma, cutaneous squamous cell carcinoma (cSCC), and Merkel cell carcinoma (MCC), present a fundamental paradox: high tumor immunogenicity coexists with profound immune evasion, driven by oncogenic signaling, an immunosuppressive microenvironment, metabolic dysregulation, and fibrotic stroma. Multifunctional nanoplatforms offer a systems-level strategy to overcome this multilayered resistance. They enable coordinated reprogramming of immune checkpoints and myeloid compartments, precise induction of immunogenic cell death through organelle-targeted stress or novel death pathways like cuproptosis, and synergistic use of photo-, ultrasound-, or magnetic-energy triggers. Concurrently, these platforms remodel the tumor microenvironment by scavenging immunosuppressive metabolites, exploiting lineage-specific metabolic vulnerabilities, and degrading fibrotic barriers to restore T-cell infiltration. The integration of computational intelligence-spanning AI-driven nanocarrier design, multi-omics-based patient stratification, and real-time biomarker monitoring-further empowers adaptive therapeutic strategies. By unifying biomimetic delivery, stimuli-responsive activation, and energy-coupled immunomodulation, advanced nanocarriers actively reconfigure tumor-immune crosstalk, demonstrating synergistic antitumor efficacy in preclinical models of melanoma, cSCC, and MCC. Successful clinical translation, however, requires addressing key challenges: scalable manufacturing of complex constructs, proactive management of cytokine-driven immunotoxicity, and robust biomarker-guided patient selection. The future of nano-immunotherapy lies in adaptive platforms that leverage liquid biopsy and computational modeling to dynamically counter the spatiotemporal evolution of resistance, offering a transformative paradigm for managing aggressive skin cancers.
Liu J, Liu X, Li Z
… +14 more, Yu X, Qian J, Zhang Z, Ding X, Su R, Mao J, Luo X, Wang S, Xie Q, Xie H, Yin S, Zhou L, Yang Z, Zheng S
Cancer Lett
· 2026 Jun · PMID 41871800
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MSR1 tumor-associated macrophages (TAMs) have been implicated in various malignancies; however, their functional role in Hepatocellular carcinoma (HCC) remains poorly defined. This research seeks to clarify the roles of...MSR1 tumor-associated macrophages (TAMs) have been implicated in various malignancies; however, their functional role in Hepatocellular carcinoma (HCC) remains poorly defined. This research seeks to clarify the roles of MSR1 TAMs in HCC and their influence on the tumor immune microenvironment. Clinical and experimental data indicate that high levels of MSR1 TAMs correlate with poor prognosis in HCC patients. Transcriptomic analyses and in vitro as well as in vivo functional assays revealed that the immunosuppressive activity of MSR1 TAMs is closely linked to their secretory profile. MSR1 enhances IL-6 secretion by activating the NF-κB signaling pathway, subsequently facilitating the recruitment of myeloid-derived suppressor cells (MDSCs). This cascade diminishes CD8 T cell infiltration and effector function, promoting an immunosuppressive tumor microenvironment. In preclinical models, the simultaneous inhibition of MSR1 and PD-L1 markedly reduced tumor growth more effectively than either treatment alone. Our findings demonstrate that MSR1 TAMs contribute to hepatocellular carcinogenesis through the NF-κB/IL-6 signaling axis by promoting MDSCs accumulation and impairing CD8 T cell responses. Effectively targeting MSR1 TAMs can overcome resistance to anti-PD-L1 therapy, offering a promising new immunotherapeutic approach for HCC.
Shen MZ, Guo LP, Mo XD
… +13 more, Yu YT, Li CY, Chen DD, Lyu ZS, Zhao HY, Wen Q, Zhang YY, Xu LP, Wang Y, Zhang XH, Liu DH, Huang XJ, Kong Y
Cancer Lett
· 2026 Jun · PMID 41862151
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Poor hematopoietic reconstitution (PHR), a serious complication after chemotherapy or radiotherapy in patients with hematological or solid malignancies, which lacks effective treatment options because its underlying path...Poor hematopoietic reconstitution (PHR), a serious complication after chemotherapy or radiotherapy in patients with hematological or solid malignancies, which lacks effective treatment options because its underlying pathogenesis remains unclear. Bone marrow macrophages (BM MΦs) are multifunctional, plastic cells essential in hematopoiesis though our previous study demonstrated distinct hematopoietic regulatory role between M1 and M2 subtypes. However, the specific phenotype of M2-MΦ and pathways involved in hematopoietic support remain unclear. Here, we identified a novel population of BM-MΦs, SELENOP MΦs, that exhibit an M2-biased phenotype with hematopoietic stem cell (HSC)-supporting ability. These cells were markedly impaired in patients with poor graft function (PGF) after allogeneic HSC transplantation, potentially because of defective autocrine GAS6-AXL (ligand-receptor) signaling. Both in vitro and BM MΦ-specific AXL knockdown mouse models confirmed that reduced AXL activity contributed to MΦ dysfunction and the downstream reduction in IGF1 secretion. Notably, treatment with GAS6 partially restored the HSC-supporting ability of impaired BM MΦ from PGF patients in vitro. Overall, our study identified an HSC-supportive SELENOP MΦ subset regulated by GAS6-AXL signaling, offering novel therapeutic insights for impaired hematopoiesis.
Kane LE, Hackett D, Lyons R
… +2 more, Ryan BM, Maher SG
Cancer Lett
· 2026 Jul · PMID 41856311
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The hallmarks of cancer and enabling characteristics are widely regarded as the key features that best define malignant disease. In a process as intricate as the development of cancer, a simple definition or stepwise ser...The hallmarks of cancer and enabling characteristics are widely regarded as the key features that best define malignant disease. In a process as intricate as the development of cancer, a simple definition or stepwise series of biological events does little to encapsulate the insurmountable complexity that is this disease. Indeed, over the course of the last 25 years alone, there have been four renditions of the "Hallmarks of Cancer", each attempting to encapsulate the mechanisms involved in the development of cancer by providing a list of strict criteria that must be met in order to define the disease. With each of these four sets of principles, modern research has caused the ensuing recapitulation to be revised, and without exception, to expand. In fact, what originally began as six hallmarks of cancer, has become a list of parameters that is fourteen strong, and which aim to summarize the functional capabilities that, when acquired by human cells, provides them with the ability to form a malignant, life-threatening tumour. While at present these hallmark capabilities have largely been discussed in the context of all cancers, this review discusses each in the specific context of pancreatic cancer (PC). PC has the worst prognosis of all cancers globally, with late-stage diagnoses, aggressive tumour microenvironments, and limited treatment options contributing to the current 5-year survival rate of 13%. Here, we highlight PC-specific mechanisms underpinning each hallmark of cancer to provide a comprehensive review of the current state of knowledge around this complex disease, with the aim of aiding understanding and facilitating more meaningful research avenues.
Liu LT, Wang H, Zhang SW
… +2 more, Shao ZM, Jiang YZ
Cancer Lett
· 2026 Jun · PMID 41850575
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Aging and cancer are intricately linked through complex, bidirectional interactions, with immune remodeling representing a central point of convergence. Although studies of immune aging have largely centered on T cells,...Aging and cancer are intricately linked through complex, bidirectional interactions, with immune remodeling representing a central point of convergence. Although studies of immune aging have largely centered on T cells, accumulating evidence indicates that B cells also undergo significant functional or phenotypic alterations during aging and tumorigenesis. Here, we introduce the concept of age-related B cell dysfunction to encompass a spectrum of changes that include impaired germinal center response, decline in B cell diversity, expansion of pro-inflammatory phenotypes, and increased autoreactivity. Aging and cancer share fundamental biological hallmarks, including genomic instability, epigenetic reprogramming, chronic inflammation, and dysbiosis, which profoundly reshape immune cell states. In this review, we synthesize emerging mechanistic evidence linking these processes to maladaptive B cell programs across tissues and tumor contexts, and discuss how such alterations influence tumor evolution, responses to therapy, and treatment-related toxicities. Finally, we highlight emerging strategies targeting age-related dysfunctional B cells in cancer, illustrating how insights from biology of aging and tumor immunology could inform future translational approaches.
Sang C, Rao D, Qin H
… +8 more, Zhang M, Luo R, Huang Y, Pan J, Lin Y, Zhang S, Lin J, Gao Q
Cancer Lett
· 2026 May · PMID 41839437
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Intrahepatic cholangiocarcinoma (iCCA), a highly lethal subtype of liver cancer with increasing incidence and poor prognosis, displays profound molecular heterogeneity that limits therapeutic efficacy. Combining multi-om...Intrahepatic cholangiocarcinoma (iCCA), a highly lethal subtype of liver cancer with increasing incidence and poor prognosis, displays profound molecular heterogeneity that limits therapeutic efficacy. Combining multi-omics with pathological subtyping in iCCA, we identified a strong association between the most aggressive molecular subtype and the large-duct pathological type, characterized by aberrant mucin overexpression and prominent myeloid cell infiltration. Through integrative analysis, MUC16 was identified as a key molecular marker specifically enriched in large-duct type intrahepatic cholangiocarcinoma (L-iCCA). Functional modulation of MUC16 markedly inhibited L-iCCA cell proliferation and migration. Furthermore, high-throughput drug screening identified the small-molecule compound OSMI-1 as a potent suppressor of MUC16 expression. Using primary iCCA cell lines and patient-derived organoids (PDOs), we confirmed that OSMI-1 inhibits L-iCCA cell proliferation and migration by downregulating MUC16. Mechanistically, OSMI-1 suppresses MUC16 expression by disrupting the transcriptional complex formed between OGT and IRF1. Employing a genetically engineered L-iCCA mouse model, we further validated the crucial role of MUC16 in tumor progression and neutrophil infiltration, demonstrated that OSMI-1 synergized with gemcitabine, effectively inhibiting L-iCCA growth. This study presents a pathological subtype-based precision therapeutic strategy for L-iCCA, thereby providing a foundation for novel translational approaches to the personalized management of this disease.
Ghosh D, White B, Lu X
… +6 more, Perricone M, Zhou M, Xuan B, Li Y, Wang Y, Dawson MR
Cancer Lett
· 2026 May · PMID 41833656
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Polyploid giant cancer cells (PGCCs) are enlarged, multinucleated tumor cells that arise in response to stressors such as chemotherapy and are increasingly recognized as key drivers of recurrence and metastasis in aggres...Polyploid giant cancer cells (PGCCs) are enlarged, multinucleated tumor cells that arise in response to stressors such as chemotherapy and are increasingly recognized as key drivers of recurrence and metastasis in aggressive cancers. Found in triple-negative breast cancer (TNBC) and ovarian cancer (OC), PGCCs can survive cytotoxic therapy in a dormant state and later produce chemoresistant progeny through amitotic budding. Here, we investigated the role of autophagy in paclitaxel (PTX)-induced PGCC survival, nuclear maintenance, and migration. PGCCs generated from MDA-MB-231 and HEY cells were significantly larger, more heterogeneous, and more resistant to PTX than parent cells. Transcriptomic profiling revealed enrichment of metabolic and cytoskeletal pathways, with strong upregulation of autophagy-related genes, including SQSTM1 (P62), LC3, and LAMP1. PGCCs exhibited elevated oxidative stress and marked induction of mitochondrial superoxide dismutase 2 (SOD2). p62 was localized near micronuclei, and prolonged autophagy inhibition with Bafilomycin A1 reduced nuclear size, heterogeneity, and micronuclei number. PGCCs also displayed a dispersed vimentin intermediate filament network that scaffolded autophagic structures; autophagy inhibition impaired migration in PGCC-derived daughter cells. These findings identify autophagy as a critical process sustaining PGCC survival, structural integrity, and motility, and suggest that targeting autophagy may disrupt PGCC-driven recurrence in aggressive cancers.
Chen Z, Feng X, Pathak JL
… +7 more, Fu Z, Chen X, Zeng L, Zheng Y, Qiu Q, Qiao L, Wu L
Cancer Lett
· 2026 May · PMID 41831519
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The crosstalk between cancer-associated fibroblasts (CAFs) and immune cells drives immunosuppressive tumor microenvironment (TME) in oral squamous cell carcinoma (OSCC), but the underlying mechanisms remain poorly unders...The crosstalk between cancer-associated fibroblasts (CAFs) and immune cells drives immunosuppressive tumor microenvironment (TME) in oral squamous cell carcinoma (OSCC), but the underlying mechanisms remain poorly understood. Here, we identified fibroblast activation protein (FAP)-expressing CAFs as the key orchestrators of immunosuppression through WNT2-mediated reprogramming of C1QC macrophages. Thus, we utilized single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, in vitro and in vivo functional assays to investigate the role of FAP fibroblasts in modulating TME. Co-culture systems and multi-omics analyses were employed to dissect stromal-immune crosstalk. Our study demonstrated that FAP expression escalated during OSCC progression and correlated with poor prognosis. According to OSCC animal model and single-cell RNA sequencing, the inhibition of FAP reshaped the immune landscape, notably reducing infiltration of C1QC macrophages, which localized proximally to FAP fibroblasts in clinical specimens. Mechanistically, FAP fibroblasts secreted WNT2 to activate β-catenin signaling in macrophages, upregulating C1QC and M2 markers. This FAP-WNT2-C1QC axis conferred tumor-promoting functions. Further analysis demonstrated that C1QC macrophages exhibited tumor-promoting functions, including enhanced fatty acid metabolism and immunosuppressive signaling. They secreted CCL2 to recruit Tregs, and induced T cell exhaustion. Crucially, FAP expression predicted resistance to anti-PD-1 therapy, and its inhibition enhanced the efficacy of anti-PD-1 treatment in OSCC. Overall, our findings unveil stromal FAP fibroblasts as central regulators of macrophage-dependent immunosuppression via WNT2 signaling, proposing a novel therapeutic target to reprogram the TME in OSCC.
Rumnieks F, Vainshelbaum NM, Salmina K
… +13 more, Lazovska M, Kreismane M, Pjanova D, Zalums J, Vaivode K, Saliba DR, Zayakin P, Freivalds T, Perminov D, Kasperski A, Scherthan H, Cragg MS, Erenpreisa J
Cancer Lett
· 2026 May · PMID 41831518
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Resistance to Vemurafenib (VEM), a targeted BRAFV600E inhibitor, was examined in the metastatic paratetraploid (XX, abnormal Y chromosome) melanoma cell line, SkMel28. During the first week of treatment, pERK suppression...Resistance to Vemurafenib (VEM), a targeted BRAFV600E inhibitor, was examined in the metastatic paratetraploid (XX, abnormal Y chromosome) melanoma cell line, SkMel28. During the first week of treatment, pERK suppression coincided with transcriptomic and phenotypic changes related to senescence, autophagy/mitophagy, neuro-melanogenesis, and cell co-alignment. By the second week, MAPK-ERK signalling was restored, coinciding with surmounting the G1/S checkpoint, G2M checkpoint delay, mitotic slippage (MS), and downregulation of senescence and melanogenesis. The dynamics of melanogenesis and MS were highly correlated. By days 12-15, ∼8% of cells with melanin remnants exhibited hyperploidy and multinucleation, some arranged as rosettes, encased by a Zona pellucida-positive structure reminiscent of oocytes, zygotes, or blastulae, occasionally yielding cellularised sub-cells or stalling in diapause. These parasexual processes eventually ceased; cells resumed proliferative clonogenic growth and their initial mito-meiotic, mesenchymal profile. Transcriptomic analysis confirmed the reversal of their cell fate direction: from senescence-induced neuro-melanogenesis to its suppression and activation of female meiosis-like and mitosis states. The transition point of this cell-fate reversal coincided with S-phase resumption, highlighted by replication delay and activation of the FOS-TEAD/Hippo axis of the "female pregnancy" (stress-response, embryonal placentation, vascularisation, stemness, anti-apoptosis) gene ontology module. We conclude that resistance to VEM in SkMel28 cells encompasses the transition between three possible cell fates: (1) senescence/differentiation, (2) reprogramming/blastulation, and (3) recovery of the proliferative mito-meiotic profile. The coexpression of senescence, reprogramming and gametogenetic genes in a dataset of late-stage melanoma patient samples supports these results.
Panesso-Gómez S, Cole AJ, Arrigo A
… +30 more, Roberts A, Bello M, Wield A, Anyaeche VI, McGonigal S, Hijazi A, Shah J, Jiang Q, Ebai T, Sharrow AC, Tseng G, Yoon E, Brown DD, Clark AM, Larsen SD, Eder I, Gau D, Roy P, Tran L, Jiang H, Sannino S, Goeckler-Fried J, Choi Y, Brodsky JL, Osmanbeyoglu H, Ma X, Dahl KN, McAuliffe PF, Lee AV, Buckanovich RJ
Cancer Lett
· 2026 May · PMID 41831517
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Chemoresistance is a major cause of cancer deaths. One understudied mechanism of chemoresistance is quiescence. We used single-cell culture to identify and isolate patient-derived proliferating and quiescent ovarian canc...Chemoresistance is a major cause of cancer deaths. One understudied mechanism of chemoresistance is quiescence. We used single-cell culture to identify and isolate patient-derived proliferating and quiescent ovarian cancer cells (qOvCa). RNA-seq analysis indicated that hundreds of genes that are differentially expressed in qOvCa cells are transcriptional targets of the Myocardin-Related Transcription Factor-A/Serum Response Factor (MRTFA/SRF) pathway, and both genetic disruption and pharmacologic inhibition of MRTFA/SRF interaction (with the inhibitor CCG257081) induced quiescence across multiple cancer types. MRTFA/SRF inhibition-mediated quiescence is p27/Kip1 dependent and associated with a downregulation of cell cycle regulators, NCL, MYH9, and alterations in the proteasome. We show that the MRTFA/SRF axis plays a dual role in chemotherapy resistance, with both pathway inhibition and activation contributing to chemotherapy resistance in vitro and in patient samples. CCG081 treatment results in a proteasome-dependent downregulation of the stem-cell marker CD133. Suggesting a critical role for the proteasome in quiescent cells, CCG081 therapy sensitized OvCa cells to proteasome inhibitors. In vivo, we found that CCG257081 therapy could be used to induce tumor growth-arrest and delay disease growth to improve overall survival. Moreover, we found that dual therapy with CCG081 and proteasome inhibition further improved outcomes, leading to undetectable tumors in ∼20% of mice. Together, these data suggest that the MRTFA/SRF pathway is a critical regulator of quiescence in cancer and a potential therapeutic target.
Martell E, Kuzmychova H, Grewal A
… +4 more, Chawla U, Jain C, Anderson CM, Sharif T
Cancer Lett
· 2026 May · PMID 41825848
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Metabolic reprogramming is a defining hallmark of cancer, and brain tumors are no exception. The brain's extraordinary energy demands, metabolic compartmentalization, and protection by the blood-brain barrier create a un...Metabolic reprogramming is a defining hallmark of cancer, and brain tumors are no exception. The brain's extraordinary energy demands, metabolic compartmentalization, and protection by the blood-brain barrier create a unique microenvironment that profoundly shapes tumor metabolism. Many brain tumors exhibit enhanced glucose uptake and fermentative glycolysis, a phenomenon classically described as the Warburg effect. However, accumulating evidence over the past two decades reveals that brain tumors rely on a far broader and more dynamic metabolic repertoire. Beyond glycolysis, metabolic processes such as the pentose phosphate pathway, serine biosynthesis, tricarboxylic acid cycle, oxidative phosphorylation, glutaminolysis, lipid metabolism, and purine and pyrimidine biosynthesis, all contribute to sustaining tumor growth, stemness, epigenetic identity, and therapeutic resistance. These metabolic adaptations differ markedly across tumor types and developmental contexts, from glioblastoma and diffuse astrocytoma to oligodendroglioma, ependymoma, pediatric high-grade glioma, medulloblastoma, and other embryonal tumors. In this review, we provide an overview of the current understanding of the major metabolic hallmarks of brain cancer, emphasizing mechanisms that support tumor identity, proliferation, and survival. We further highlight emerging metabolic vulnerabilities and discuss progress in developing therapies that target these pathways. Together, these insights illuminate how metabolism underpins the remarkable adaptability of brain tumors and suggest new avenues for precision treatment.