Molecular Cancer[JOURNAL]
Sun
200 papers
STING-Activating nanoplatforms for image-guided sonodynamic cancer therapy.
Zhang L, Huang D, Li J … +8 more , Mo L, Qin T, Xing B, Xiao B, Xu C, Xiao H, Zeng L, Shang K
Mol Cancer · 2026 Feb · PMID 41664042 · Full text
Tumor precision treatment still faces the challenge of being unable to achieve real-time monitoring. The rapid advancements in nanomedicine within the biomedical sector have highlighted the potential of integrated nano-p...
Tumor precision treatment still faces the challenge of being unable to achieve real-time monitoring. The rapid advancements in nanomedicine within the biomedical sector have highlighted the potential of integrated nano-platforms for tumor diagnosis and treatment. Herein, we create a multimodal diagnostic nanodrug, ⁹⁹Tc-NP-MSA, which combines sonosensitizers, STING agonists, and radionuclides for immuno-sonodynamic therapy targeting breast cancer. This platform utilizes polymers with aggregation-induced luminescence properties that, when activated by US, generate cytotoxic reactive oxygen species, causing DNA and mitochondrial damage, activating the cGAS-STING pathway, and releasing the STING agonist MSA-2 to enhance the immune response. Additionally, ⁹⁹Tc incorporation facilitates SPECT/CT and near-infrared fluorescence imaging, thereby improving tumor targeting and therapeutic monitoring precision. Both in vitro and in vivo studies confirm the significant anti-tumor effects and immunomodulation achieved by this nano-platform under US, presenting a novel strategy for precise tumor diagnosis and treatment.
Correction: The chromosome 11q13.3 amplification associated lymph node metastasis is driven by miR-548k through modulating tumor microenvironment.
Zhang W, Hong R, Li L … +11 more , Wang Y, Du P, Ou Y, Zhao Z, Liu X, Xiao W, Dong D, Wu Q, Chen J, Song Y, Zhan Q
Mol Cancer · 2026 Feb · PMID 41656277 · Full text
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Correction: Histone demethylase KDM4D promotes gastrointestinal stromal tumor progression through HIF1β/VEGFA signalling.
Hu F, Li H, Liu L … +5 more , Xu F, Lai S, Luo X, Hu J, Yang X
Mol Cancer · 2026 Feb · PMID 41656223 · Full text
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Therapeutic reprogramming of tumour-associated macrophages in pancreatic cancer using a cytotoxic CCR2-targeted nanotheranostic.
Somani VK, Zhang X, Chen TH … +14 more , Bulle A, Bansod S, Li L, Geng Y, Kang LI, Heo GS, Luehmann H, Zhang Y, Saeed MA, Lavine KJ, DeNardo DG, Pachynski RK, Liu Y, Lim KH
Mol Cancer · 2026 Feb · PMID 41654815 · Full text
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) exhibits a profoundly immunosuppressive tumour microenvironment (TME) dominated by inflammatory monocytes (IMs) and tumour-associated macrophages (TAMs), which restrict...
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) exhibits a profoundly immunosuppressive tumour microenvironment (TME) dominated by inflammatory monocytes (IMs) and tumour-associated macrophages (TAMs), which restrict adaptive immunity and drive resistance to immune checkpoint blockade (ICB). Recruitment of CCR2⁺ IMs by tumour-derived CCL2 is a central mechanism underlying TAM accumulation. Conventional gemcitabine (GEM) and small-molecule CCR2 inhibitors provide limited benefit due to poor intratumoural delivery, transient target engagement, and compensatory myeloid recruitment. METHODS: We engineered a CCR2-targeted nanotheranostic by conjugating a CCR2-binding peptide (ECL1i) and GEM onto ultrasmall copper nanoclusters (CuNCs-ECL1i-GEM; C-E-G). Therapeutic efficacy and immune remodelling were evaluated using orthotopic subcutaneous and the autochthonous PDAC mouse models model, using scRNAseq, flow cytometry, multiplex immunohistochemistry, and in vitro functional assays. RESULTS: C-E-G exhibited robust tumour accumulation and selectively eliminated CCR2⁺ TAMs without systemic myelotoxicity, while durably reprogramming residual macrophages. Mechanistically, C-E-G induced the emergence of an immunostimulatory CCRL2⁺ TAM subset through true macrophage repolarization rather than monocyte replacement. CCRL2⁺ TAMs accumulated intratumoural chemerin, upregulated antigen-presentation and co-stimulatory programs, and were essential for CD8⁺ T-cell recruitment and activation. Genetic and orthotopic studies confirmed their CCR2-independent origin and requirement for tumour control. C-E-G remodelled the TME toward a lymphocyte-permissive inflammatory state and synergized with ICB to induce complete tumour regression and prolong survival in KPPC mice. CONCLUSIONS: CCR2-targeted cytotoxic nanotherapy eliminates immunosuppressive CCR2 + TAMs, reprograms the macrophage landscape including CCRL2⁺ TAMs, and unlocks durable anti-tumour immunity in PDAC, supporting translational development of this strategy.
Identification of HSPE1 as a new actionable cancer vulnerability leads to an innovative and effective combination therapy for pancreatic ductal adenocarcinoma.
Boudreault J, Rahimirad S, Wang N … +6 more , Yan G, Lima LC, Poulet S, Dai M, Ali S, Lebrun JJ
Mol Cancer · 2026 Feb · PMID 41645202 · Full text
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest human malignancies, with limited therapeutic options and a lack of druggable vulnerabilities beyond a narrow set of oncogenic drivers. To identify canc...
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest human malignancies, with limited therapeutic options and a lack of druggable vulnerabilities beyond a narrow set of oncogenic drivers. To identify cancer dependencies that are both essential in vivo and drug-tractable, we performed an unbiased genome-wide CRISPR loss-of-function screen under in vivo tumor-selective pressure. This approach revealed the mitochondrial co-chaperone HSPE1 (Hsp10) as a previously unrecognized, tumor-promoting dependency in PDAC. Genetic depletion of HSPE1 markedly impaired tumor growth, survival, and tumor-initiating capacity across multiple PDAC models in vitro and in vivo, including patient-derived xenografts. Mechanistically, HSPE1 functioned as a central survival node by engaging two parallel and targetable mitochondrial pathways. First, HSPE1 cooperated with its canonical partner HSPD1 to regulate cell-cycle progression, and apoptosis. Second, HSPE1 was functionally associated with mitochondrial dynamics, correlating with altered regulation of the OPA1/OMA1 axis, revealing an HSPD1-independent mechanism linking mitochondrial stress adaptation to cancer cell fitness. This dual signaling architecture exposes a previously unappreciated mitochondrial vulnerability selectively exploited by PDAC cells. Importantly, both HSPE1-regulated pathways were amenable to therapeutic targeting in vivo. Pharmacological inhibition of the HSPD1/HSPE1 complex or the OPA1/OMA1 pathway significantly suppressed tumor growth, while combined targeting produced robust synergistic antitumor activity in both cell line–derived and patient-derived PDAC models. Moreover, this combination strategy provides a modest yet consistent incremental benefit to standard-of-care chemotherapies, underscoring its translational relevance. Together, these findings establish HSPE1 as a bona fide cancer dependency uncovered through in vivo functional genomics, uncover a dual mitochondrial vulnerability, and provide a rational framework for combination therapy design. More broadly, this work highlights the power of in vivo CRISPR screening to directly inform therapeutic strategies and identifies mitochondrial stress adaptation as a promising and generalizable target in cancer.
An oncogenic KRAS-driven secretome involving TNFα promotes niche preparation prior to pancreatic cancer onset.
Allgöwer C, Mulaw MA, Nagai J … +32 more , Wiedenmann S, Ringel EA, Ferrara B, Piemonti L, Maulana TI, Ferreira LT, Flinders A, Teufel C, Reichardt L, Lopatta PB, Srinivasan D, Lahusen A, Seufferlein T, Gaisa NT, Beck A, Lindenmayer J, Melzer MK, Zimmer E, Roger E, Heller S, Löhr JM, Liebau S, Loskill P, Lin YN, Camisa PR, Jorgensen C, Crippa S, Meier M, Hohwieler M, Costa IG, Breunig M, Kleger A
Mol Cancer · 2026 Feb · PMID 41634803 · Full text
BACKGROUND: Pancreatic ductal adenocarcinomas (PDACs) are highly lethal and aggressive with oncogenic KRAS being the main oncogenic driver of the disease. PDACs have been extensively profiled at advanced stages, and in a...
BACKGROUND: Pancreatic ductal adenocarcinomas (PDACs) are highly lethal and aggressive with oncogenic KRAS being the main oncogenic driver of the disease. PDACs have been extensively profiled at advanced stages, and in advanced disease the tumor microenvironment is a major determinant that critically shapes patient outcomes. Since the molecular events occurring prior to invasive growth remain poorly understood, we aimed to investigate changes in the precancerous epithelium and its surrounding niche. METHODS: We acquired time-resolved, single-cell transcriptomic (scRNAseq), and accessible-chromatin data from human pluripotent stem cell-derived pancreatic duct-like organoids (PDLO) inducibly expressing KRASG12D and from various niche cells. RESULTS: Analysis of the pure epithelium already revealed key signatures of matrix remodeling and inflammation-related signaling upon few days of KRASG12D expression. Machine learning captured KRASG12D-dependent transcriptomic classifiers with high prediction accuracy and niche preparatory relevance. Various co-culture approaches followed by scRNAseq and functional validation, including T-cell microfluidics, demonstrated that the KRASG12D-induced PDLO-secretome activates pancreatic stellate cells (PaSCs) and protects precancerous organoids from T cell infiltration. Additional, in silico approaches reconstructed a virtual pancreatic (pre)cancerous space to profile cell–cell interactions between PDLOs and niche cells. TNFα emerged as a top-ranked ligand and was functionally validated to mediate T-cell shielding and PaSC activation. Cyst fluid from 80 prospectively sampled Intraductal Papillary Mucinous Neoplasm (IPMNs) –well-known cystic PDAC precursor lesions– showed a stepwise TNFα rise across LGD (low-grade), HGD (high-grade), and IC (invasive cancer). CONCLUSION: Our study reveals that oncogenic KRAS orchestrates niche-preparatory programs that precede PDAC formation and highlight a T cell exclusion program governed by epithelial-derived TNFα.
Fusobacterium nucleatum manipulates host autophagy to promote its intracellular survival and treatment resistance in nasopharyngeal carcinoma.
Wang JY, Lu YQ, Tan XR … +13 more , Ma SS, Dai JH, Feng SY, Duan YF, Bai JW, Li YQ, Gong S, Liang YL, Huang SW, Ma J, Xu C, Li JY, Liu N
Mol Cancer · 2026 Feb · PMID 41634790 · Full text
BACKGROUND: Growing evidence highlights the existence and tumor-promoting role of intratumoral bacteria in various types of cancers. However, the mechanisms enabling the intracellular survival of these microorganisms rem...
BACKGROUND: Growing evidence highlights the existence and tumor-promoting role of intratumoral bacteria in various types of cancers. However, the mechanisms enabling the intracellular survival of these microorganisms remain poorly understood, impeding the development of microbiota-targeting anticancer strategies. METHODS: A transcriptomics analysis was used to identify the disease-related bacteria in nasopharyngeal carcinoma (NPC). Cell-bacteria coculture assay, cell viability assay, and mouse xenograft tumor model were used for functional investigation. Immunofluorescence, quantitative PCR analysis, RNA sequencing, immunoblot analysis, co-immunoprecipitation and mass spectrometry were utilized in mechanistic research. Fluorescent in situ hybridization in NPC specimens and clinical data were used for prognosis analysis. RESULTS: We discovered that the Fusobacterium nucleatum (F. nucleatum), especially the C2 clade of F. nucleatum subsp. animalis (Fna C2), acts as an intracellular pathogen and exhibits distinct colonization advantages in NPC by inhibiting autophagy flux in host cells. Mechanistically, the virulence protein FadA of Fna C2 increases the ubiquitination and promotes the degradation of Ras-related protein RAB7A by enhancing the interaction between RAB7A and the E3 ligase TRIM28, which thus impairs the autophagosome-lysosome fusion and the autophagy machinery. The dysfunctional autophagy not only enables the persistent intracellular survival of F. nucleatum but also contributes to the treatment resistance of NPC. Clinically, a high intratumoral F. nucleatum colonization is associated with tumor relapse and poor outcome in NPC patients. CONCLUSION: Our findings elucidate a key mechanism by which F. nucleatum survives and promotes treatment resistance in NPC, providing a microbiological prognosis indicator for NPC patients.
Metabolic reprogramming in cancer: signaling pathways and therapeutic targets.
Dong S, Li T
Mol Cancer · 2026 Feb · PMID 41634663 · Full text
Metabolism is a general term for an ordered series of chemical reactions used to maintain life, and the maintenance of normal cellular activities cannot be separated from metabolism, which is the most basic feature of li...
Metabolism is a general term for an ordered series of chemical reactions used to maintain life, and the maintenance of normal cellular activities cannot be separated from metabolism, which is the most basic feature of life. However, metabolic alterations have a dual role. In normal cells, metabolic dysregulation predisposes them to impaired energy acquisition, senescence and even apoptosis. In contrast, metabolic remodeling in tumor cells is advantageous for cancer cell growth and proliferation, driving tumor development and becoming a hallmark of cancer. The inherent heterogeneity and plasticity of many tumor cells themselves are often accompanied by unique alterations in energy metabolism that allow them to survive even in harsh environments where resources are scarce. Notably, tumor cells do not operate in isolation; their metabolic reprogramming is tightly intertwined with metabolic crosstalk and collaborative adaptations involving other components within the tumor microenvironment. Among these metabolic pathways, glycolysis remains the dominant metabolic pathway driving tumor growth and microenvironmental remodeling, even under oxygen-sufficient conditions. Additionally, amino acid, lipid, and polyamine metabolism have been identified as a metabolic regulators that support cancer cell growth, influencing the fate and function of other cells in the microenvironment through metabolite exchange. Targeting cancer metabolism and its interactions with the microenvironment has thus emerged as a promising strategy for treating various malignancies. This article systematically reviews the redistribution of metabolic activities during cancer progression, encompassing both cell-autonomous metabolic reprogramming and microenvironment-mediated metabolic synergy and adaptation. The aim is to provide novel insights and therapeutic strategies for the comprehensive treatment of cancer.
Tumor microenvironment dynamics in gastric cancer pathogenesis and therapeutic resistance.
Lu Z, Zhang Q, Han J … +2 more , Ji J, Xing X
Mol Cancer · 2026 Feb · PMID 41630007 · Full text
Gastric cancer remains a significant global health challenge due to its high incidence and mortality, and limited treatment options in advanced stages. Notably, gastric cancer exhibits a complex tumor microenvironment (T...
Gastric cancer remains a significant global health challenge due to its high incidence and mortality, and limited treatment options in advanced stages. Notably, gastric cancer exhibits a complex tumor microenvironment (TME) with substantial cellular and spatial heterogeneity, which profoundly impacts disease pathogenesis and therapeutic resistance. Genetic mutations and chronic inflammation contribute to its development by promoting abnormal cell proliferation and creating an immunosuppressive TME. The TME comprises various cellular and acellular components—including tumor-infiltrating lymphocytes, myeloid lineage cells such as tumor-associated macrophages and myeloid-derived suppressor cells, cancer-associated fibroblasts, extracellular matrix, and peripheral nerves—that interact with cancer cells, influencing tumor initiation, progression, immune evasion, and resistance to therapy. These elements modulate immune responses, remodel the extracellular matrix, and facilitate tumor growth and metastasis, thereby adding to the complexity of the TME. Moreover, the TME plays a critical role in therapeutic resistance through mechanisms involving angiogenesis, fibrosis, and metabolic reprogramming. Understanding the dynamic interactions within the TME offers opportunities to develop novel therapeutic strategies. Emerging approaches targeting the TME—including modulation of immune components, inhibition of fibrosis, normalization of angiogenesis, and disruption of metabolic pathways—hold promise in overcoming therapeutic resistance. Advances in technologies such as single-cell sequencing and spatial transcriptomics further enhance our understanding of TME heterogeneity, paving the way for personalized medicine in gastric cancer treatment. This review summarized the current knowledge of the cellular and molecular composition of the TME of gastric cancer, its role in disease pathogenesis and therapy resistance, and explores potential therapeutic strategies targeting TME components.
Single-cell omics in tumor lymph node metastasis: mechanisms and therapeutic implications.
Liu X, Meng X, Liu Z … +3 more , Cao L, Gan L, He Y
Mol Cancer · 2026 Feb · PMID 41629958 · Full text
Lymph node metastasis (LNM) represents a distinctive stage in cancer progression, exerting a profound impact on patient prognosis. Accumulating studies have unveiled that tumor-draining lymph nodes (TDLNs) play a pivotal...
Lymph node metastasis (LNM) represents a distinctive stage in cancer progression, exerting a profound impact on patient prognosis. Accumulating studies have unveiled that tumor-draining lymph nodes (TDLNs) play a pivotal role in immunotherapy, functioning as an armory for anti-tumor immunity. Concurrently, LNM itself accelerates systemic metastatic progression, exacerbates systemic immunosuppression, and in turn fuels tumor progression. Recent advancements in single-cell sequencing technology have furnished insights into the mechanisms of LNM at single-cell resolution, unraveling the process of LNM in tumor cells and accompanying microenvironmental alterations from the perspectives of cellular heterogeneity, intercellular communication, and cellular evolutionary trajectories. Furthermore, single-cell sequencing studies have underscored the critical role of TDLNs in immunotherapy and their corresponding adaptive modifications. This article reviews the LNM microenvironment and immunosuppressive mechanisms revealed by single-cell sequencing technology, summarizes the novel targets for LNM and the current status of LNM-related immunotherapy research, and outlines the current challenges and future development directions from both technological and research content perspectives.
CircKIAA1617 promotes stemness via USP14/PGRMC1-mediated autophagy and lipid metabolism reprogramming in ER-positive breast cancer.
Yang J, Li Y, Wang Z … +14 more , Sun Y, He Y, Niu T, Liang Y, Chen X, Chen T, Han D, Zhang N, Zhao W, Chen B, Wang L, Luo D, Li X, Yang Q
Mol Cancer · 2026 Jan · PMID 41620724 · Full text
BACKGROUND: Breast cancer (BC) is the most common neoplasm in women, and its growth mainly depends on estrogen, but the mechanism of estrogen in BC is still not fully understood. Circular RNAs (circRNAs) represent a nove...
BACKGROUND: Breast cancer (BC) is the most common neoplasm in women, and its growth mainly depends on estrogen, but the mechanism of estrogen in BC is still not fully understood. Circular RNAs (circRNAs) represent a novel type of regulatory RNA characterized by high evolutionary conservation and stability. This study aimed to investigate the roles and mechanisms of circRNAs in ER-positive BC. METHODS: CircKIAA1617 was identified through high-throughput RNA sequencing in ER-positive BC. Gain- and loss-of-function assays were performed to evaluate the functions of circKIAA1617 in ER-positive BC cells. Chromatin immunoprecipitation (ChIP) and luciferase assays verified the regulatory effects of estrogen on circKIAA1617 expression. RNA pulldown experiments, proteomic analyses, and RNA immunoprecipitation were conducted to identify the downstream targets of circKIAA1617. RESULTS: CircKIAA1617 expression was upregulated in ER-positive BC cells and tissues, indicating an unfavorable prognosis. In vitro and in vivo studies proved the circKIAA1617 increased the proliferation and stemness of ER-positive BC cells by inducing autophagy. Mechanistically, circKIAA1617 was activated by estrogen and cyclized by EIF4A3. Moreover, circKIAA1617 could act as a scaffold to enhance the interaction between the PGRMC1 and USP14 proteins, further increasing the stability of the PGRMC1 protein by decreasing its K48-linked polyubiquitination at lysine 105. In addition, autophagy activated by the circKIAA1617/USP14/PGRMC1 axis further modulated lipid metabolic reprogramming in ER-positive BC by increasing lipophagy, which accounted for the proliferation, stemness and autophagy of ER-positive BC. CONCLUSIONS: Our results revealed that circKIAA1617 promoted the proliferation and stemness of BC cells by regulating USP14/PGRMC1-mediated autophagy and lipid metabolic reprogramming and could serve as a potential diagnostic biomarker for ER-positive BC.
DCLK1 drives malignant progression and chemoresistance of bladder cancer by deubiquitinating HDAC6.
Du A, Zhou Y, Deng X … +9 more , Yuan D, Li K, Luo Y, Tan S, Dai X, Yu B, Jiang K, Tan X, Zhu J
Mol Cancer · 2026 Jan · PMID 41618382 · Full text
BACKGROUND: Bladder cancer (BC) is the most common malignancy of the urinary system, with rising incidence and mortality. Advanced BC frequently recurs or metastasizes and is often refractory to curative surgical interve...
BACKGROUND: Bladder cancer (BC) is the most common malignancy of the urinary system, with rising incidence and mortality. Advanced BC frequently recurs or metastasizes and is often refractory to curative surgical intervention. Although cisplatin-based chemotherapy remains the standard first-line treatment, its clinical efficacy is frequently compromised by the development of drug resistance. Elucidating the molecular mechanisms underlying chemoresistance and metastasis is therefore critical for improving therapeutic strategies. METHODS: Single-cell RNA sequencing (scRNA-seq) was conducted to assess intratumoral heterogeneity and identify expression programs associated with bladder cancer progression. DCLK1 emerged as a key cancer-related hub gene. Its role in metastasis, cisplatin resistance, and immune evasion was evaluated using sphere formation, CCK-8, Transwell, CFSE staining, and flow cytometry assays. The interaction between DCLK1, USP10, and HDAC6 was confirmed through RNA pull-down, co-immunoprecipitation, mass spectrometry, cell localization, and molecular docking. Finally, the therapeutic potential of DCLK1, cisplatin, and ACY-1215 (an HDAC6 inhibitor) was tested in vivo. RESULTS: We identified multiple cell types, including cancer cells, lymphocytes, myeloid cells, fibroblasts, and other stromal components. In cancer cells, six biologically relevant expression programs were revealed. Among key cancer-related genes, DCLK1 was notably enriched and promoted bladder cancer metastasis, cisplatin resistance, and stemness. Mechanistically, DCLK1 activated the Notch pathway to upregulate PD-L1, suppress CD8⁺ T cell activity, and promote immune evasion. It also facilitated USP10-HDAC6 interaction, removing K48-linked ubiquitin at Lys116 to prevent HDAC6 degradation. Importantly, HDAC6 depletion abrogated the oncogenic effects of DCLK1, whereas inhibition of DCLK1 suppressed tumor progression and enhanced the antitumor efficacy of combined cisplatin and ACY-1215 treatment. CONCLUSIONS: DCLK1 is a critical driver of bladder cancer progression, chemoresistance, and immune escape. Single-cell analysis and functional assays revealed that DCLK1 enhances metastasis and stemness by activating the Notch/PD-L1 axis and stabilizing HDAC6 through USP10 interaction. Targeting DCLK1, alone or in combination with cisplatin and HDAC6 inhibition, represents a promising therapeutic strategy for advanced bladder cancer.
Platinum-based functional nanomaterials: mechanisms and therapeutic strategies in cancer radiotherapy sensitization.
Cheng Y, Mou Y, Wang H … +10 more , Shen H, Hu Y, Song X, Zhang M, Wang Y, Liu W, Yang T, Ren C, Yan M, Song X
Mol Cancer · 2026 Jan · PMID 41612402 · Full text
Radiotherapy (RT) is an important treatment option for cancer. However, its efficacy is limited by tumor radioresistance caused by hypoxic microenvironments, overactivated DNA damage repair mechanisms in tumor cells, and...
Radiotherapy (RT) is an important treatment option for cancer. However, its efficacy is limited by tumor radioresistance caused by hypoxic microenvironments, overactivated DNA damage repair mechanisms in tumor cells, and unavoidable radiation-induced injury to surrounding normal tissues. In recent years, platinum-based functional nanomaterials (PFNs) have emerged as promising radiosensitizers because of their remarkable photoelectric attenuation characteristics and unique chemical and biological properties. Considerable attention has been devoted to elucidating the mechanisms by which PFNs enhance radiosensitivity and to optimizing their design for improved targeting accuracy and radiosensitization efficiency. In this review, we systematically summarize the radiosensitization mechanisms mediated by PFNs, exploring their principles from physical, biological, and biochemical perspectives. We also discuss common strategies for designing radiosensitizing PFNs, review recent advances in their application for tumor RT sensitization, and highlight their clinical potential and current challenges. This review provides a reference for the further development and clinical translation of PFNs in RT.
The molecular mechanisms of pyroptosis and its implications in tumor immunotherapy.
Chen G, Zhang Z, Chong W … +10 more , Qiu G, Li Z, Yang S, Pan X, Ma T, Lian G, Wang X, Li L, Tian F, Jing C
Mol Cancer · 2026 Jan · PMID 41606590 · Full text
Pyroptosis is a form of programmed cell death driven by inflammatory caspases (caspase-1/4/5/11). Distinct from apoptosis, pyroptosis is characterized by the formation of membrane pores, cell swelling followed by rupture...
Pyroptosis is a form of programmed cell death driven by inflammatory caspases (caspase-1/4/5/11). Distinct from apoptosis, pyroptosis is characterized by the formation of membrane pores, cell swelling followed by rupture, and the release of cellular contents, along with the secretion of a wide range of pro-inflammatory cytokines. Pyroptosis can be activated through two primary pathways: the canonical pathway (caspase-1-dependent) and the non-canonical pathway (caspase-4/5/11-dependent). In recent years, the role of pyroptosis in tumor initiation, progression, and therapy has drawn significant attention, revealing its dual regulatory effects—both anti-tumor and tumor-promoting—highlighting its potential as a novel therapeutic target. Given its pivotal role in modulating anti-tumor immunity, the induction of pyroptosis emerges as a promising strategy to enhance the effectiveness of immunotherapy. To date, an increasing number of studies have explored the synergistic potential of combining pyroptosis-inducing strategies with immunotherapy, particularly immune checkpoint blockade, in cancer treatment.This review explores the molecular mechanisms underlying pyroptosis, and systematically summarizes the emerging evidence supporting pyroptosis as an immunogenic form of cell death that enhances immune checkpoint blockade efficacy and offers promising prospects for combination cancer therapies.
Metabolic reprogramming-driven resistance to multi-kinase inhibitors in hepatocellular carcinoma: molecular mechanisms and therapeutic opportunities.
Li J, Huang Y, Li J … +4 more , Shi M, Xiao Y, Du F, Hu G
Mol Cancer · 2026 Jan · PMID 41593671 · Full text
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is frequently diagnosed at advanced stages, limiting curative options. Multi-kinase inhibitors (MKIs), such as sorafenib and lenvatinib, serve...
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is frequently diagnosed at advanced stages, limiting curative options. Multi-kinase inhibitors (MKIs), such as sorafenib and lenvatinib, serve as first-line therapies for unresectable HCC. However, the widespread development of drug resistance significantly diminishes the clinical efficacy of MKIs, and current treatments lack effective strategies to enhance MKI sensitivity. Metabolic reprogramming, a hallmark of cancer cells that facilitates unchecked growth and metastasis, has emerged as a critical mechanism driving MKI resistance in HCC. This review comprehensively examines the roles of glycolysis, lipid metabolism, and amino acid metabolism in promoting MKI resistance, with a focus on key molecular regulators that could serve as potential targets to reverse resistance. Additionally, this review synthesizes preclinical and clinical evidence of therapeutic agents that synergize with MKIs by modulating metabolic pathways, and discusses the regulatory role of metabolic reprogramming in the tumor immune microenvironment (TIME) of HCC, offering innovative strategies to improve treatment outcomes for patients with HCC. These findings highlight metabolic reprogramming as a crucial target for developing novel interventions aimed at overcoming MKI resistance in clinical practice.
Mechanisms of tumor-derived extracellular vesicle-mediated immunometabolic reprogramming and immunotherapeutic resistance.
Zeng H, Zhang R, Zhu X … +2 more , Shen S, Zou H
Mol Cancer · 2026 Jan · PMID 41593635 · Full text
BACKGROUND: Tumor-derived extracellular vesicles (tEVs) are emerging as pivotal mediators of intercellular communication within the tumor microenvironment (TME). Beyond carrying oncogenic cargo, tEVs dynamically reprogra...
BACKGROUND: Tumor-derived extracellular vesicles (tEVs) are emerging as pivotal mediators of intercellular communication within the tumor microenvironment (TME). Beyond carrying oncogenic cargo, tEVs dynamically reprogram immune and metabolic networks that shape tumor progression and therapeutic response. MAIN BODY: In this review, we delineate how tEV-mediated immunometabolic rewiring orchestrates resistance to immunotherapy. We summarize recent findings that demonstrate how tEVs remodel glucose, lipid, and amino acid metabolism in immune cells, which in turn generates immunosuppressive microenvironments. These tEV-driven changes give rise to “metabolic checkpoints,” a newly recognized layer of immune regulation parallel to classical immune checkpoints. We further discuss how these metabolic alterations contribute to both primary and acquired immunotherapeutic resistance. Finally, we outline potential therapeutic strategies—including targeting tEV biogenesis, blocking tEV–immune interactions, and modulating metabolic checkpoints—and highlight how artificial intelligence (AI)-integrated tEV profiling and liquid biopsy may enable patient stratification and precision intervention. CONCLUSIONS: Understanding how tEV-mediated metabolic regulation shapes immune escape provides conceptual and translational opportunities. Integrating AI-driven analytics with tEV-based diagnostics may transform the prediction and reversal of immunotherapeutic resistance.
Targeting mitochondrial homeostasis as a cancer treatment strategy: current status and future prospects.
Zhong H, Pan R, Ouyang Y … +7 more , Xiao T, Gu W, Yang H, Wang H, Li H, Peng T, Chen P
Mol Cancer · 2026 Jan · PMID 41593460 · Full text
Mitochondria are central to health and disease by precisely regulating metabolism and interacting closely with other organelles. Mitochondrial dysfunction contributes to the initiation and development of numerous disease...
Mitochondria are central to health and disease by precisely regulating metabolism and interacting closely with other organelles. Mitochondrial dysfunction contributes to the initiation and development of numerous diseases, including cancer. In cancer cells, metabolic reprogramming, impaired mitochondrial quality control, and mitochondrial DNA damage are linked to tumor initiation, development, and metastasis. Dysregulated mitochondrial function in cells within the tumor microenvironment, such as CD8 + T cells, also promotes cancer progression. Therapeutic approaches targeting mitochondria range from dietary interventions to small-molecule drugs aimed at restoring mitochondrial dysfunction. In this review, we summarize the relationships between mitochondrial dysfunction and cancer from the perspectives of metabolism, quality control, mitochondrial DNA stability, ion homeostasis, and the tumor microenvironment. We also provide updates on mitochondria-targeted therapies, highlighting key translational gaps from bench to bedside. Finally, we discuss future directions for mitochondria-targeted cancer therapy, emphasizing mitochondrial homeostasis as a critical target for improving therapeutic outcomes.
Spatiotemporal dynamics of tumor-associated neutrophils: bridging the gap between cancer progression and immunotherapy.
Chu X, Ma J, Li S … +3 more , Wang M, Tian Y, Lv C
Mol Cancer · 2026 Jan · PMID 41582133 · Full text
Neutrophils, traditionally regarded as short-lived first responders of innate immunity, have emerged as pivotal regulators within the tumor microenvironment (TME). Recent advances reveal that tumor-associated neutrophils...
Neutrophils, traditionally regarded as short-lived first responders of innate immunity, have emerged as pivotal regulators within the tumor microenvironment (TME). Recent advances reveal that tumor-associated neutrophils (TANs) and neutrophil extracellular traps (NETs) exhibit remarkable spatiotemporal heterogeneity, with their phenotypes and functions dynamically evolving across tumor developmental stages and anatomical niches. TANs and NETs display dual and context-dependent roles: they can promote tumor progression via immune suppression, angiogenesis, extracellular matrix remodeling, and metastatic niche formation, yet also exert anti-tumor functions through cytotoxicity and antigen presentation under specific microenvironmental cues. This review systematically dissects the spatial and temporal dynamics of TANs and NETs, emphasizing their molecular regulation by tumor-derived secretomes, chemokine gradients, hypoxia, stromal interactions, and inflammatory signaling networks. We further delineate the bidirectional crosstalk between TANs and other immune or stromal components that contributes to immune evasion and therapy resistance. Beyond mechanistic insights, we highlight emerging therapeutic strategies, ranging from chemokine axis blockade and phenotypic reprogramming to NETs inhibition and clearance, that hold promise for disrupting neutrophil-mediated tumor support. Finally, we advocate for the integration of cutting-edge spatial and single-cell multi-omics, imaging cytometry, and AI-assisted spatial modeling to enable high-resolution mapping of neutrophil dynamics in situ and to guide precision immunotherapy.
Local metastatic expansion versus secondary intra-organ dissemination: two causes of neurological death explained by fundamentally different metastatic colonization patterns.
Komljenovic D, Bäuerle T, Alves-de-Lima J … +12 more , Trigueros L, Dietz C, Winter Z, Araceli T, Strotzer Q, Wendl C, Brendel M, Proescholdt MA, Harter PN, Evert K, Pukrop T, Blazquez R
Mol Cancer · 2026 Jan · PMID 41580751 · Full text
BACKGROUND: Neurological failure contributes to 15-50% of deaths in patients with brain metastases, yet the underlying mechanisms remain poorly understood. Clinical causes range from local compression to meningeal metast...
BACKGROUND: Neurological failure contributes to 15-50% of deaths in patients with brain metastases, yet the underlying mechanisms remain poorly understood. Clinical causes range from local compression to meningeal metastasis. In this context, a link between infiltrative histopathological growth patterns (HGPs) and meningeal metastasis was recently described and prompted this reverse translation study. METHODS: We conducted a retrospective postmortem histological assessment and a prospective MRI-based proof-of-concept study to explore neurological decline mechanisms in two experimental brain metastasis models with different HGPs: (i) the non-infiltrative TUBO model, characterized by well-defined tumor borders and a multilayered astrocytic capsule; and (ii) the infiltrative E0771-LG model, exhibiting diffuse infiltration and widespread astrogliosis. RESULTS: In the TUBO model, neurological death resulted from local metastatic expansion compressing vital structures, while the E0771-LG model caused mortality mainly through widespread secondary dissemination. We provide the first direct evidence of contralateral recolonization by secondary metastasis-initiating cells (secMICs), and highlight the high efficiency of secondary spread. Additionally, we show that secMICs exploit distinct anatomical structures to reach distant brain regions, bypassing classical vascular dissemination routes. Notably, the HGP and its associated features are intrinsic to tumor cells and are established early during metastatic colonization. CONCLUSIONS: This study identifies the HGP as a potential surrogate for predicting the underlying cause of organ failure in brain metastases. Additionally, it highlights the significant role of secondary dissemination and recolonization in brain metastasis, processes that have been largely overlooked in clinical practice. These findings address a critical knowledge gap and may inform future treatment strategies.
A paracrine-to-autocrine shunt of GREM1 fuels colorectal cancer metastasis via ACVR1C.
Zhou H, Jin Q, Fu Z … +21 more , Yang Y, Gao Y, Wang N, Zhao B, Gui L, Li J, Zhu Z, Zhang Y, He Y, Zhang Y, Luo S, Fu L, Wu X, Wang G, Xu Z, Li H, Zhang J, Shen X, Wang T, Jiang Y, Li N
Mol Cancer · 2026 Jan · PMID 41578299 · Full text
BACKGROUND: Tumor cells typically rely on paracrine stromal signals to guide malignant behavior, yet whether they gain signaling autonomy and thereby reduce microenvironment dependency during metastasis remains unclear....
BACKGROUND: Tumor cells typically rely on paracrine stromal signals to guide malignant behavior, yet whether they gain signaling autonomy and thereby reduce microenvironment dependency during metastasis remains unclear. METHODS: Gremlin 1 (GREM1) and activin A receptor type 1C (ACVR1C) expression levels and cellular distribution were analyzed by immunohistochemistry, immunofluorescence (IF) staining, and single-cell transcriptomics in colorectal cancer (CRC) specimens across stages I–IV. The GREM1–ACVR1C interaction was identified and validated by interaction proteomics, co-immunoprecipitation, IF, and microscale thermophoresis (MST). Functional roles of the GREM1–ACVR1C axis in epithelial–mesenchymal transition (EMT) and metastasis were examined by transcriptomic profiling, pathway analysis, immunoblotting, reverse transcription quantitative PCR (RT–qPCR), scratch and transwell assays, and genetically engineered and xenograft mouse models. An inhibitory peptide targeting the GREM1–ACVR1C interface was designed and evaluated. RESULTS: While GREM1 remains restricted to stromal cells in earlier-stage (I–III) CRC, its ectopic expression in tumor epithelium increases markedly in stage IV. Mechanistically, we identify ACVR1C as a direct, high-affinity epithelial receptor for GREM1. Their interaction, independent of canonical transforming growth factor β receptor (TGFβR) and bone morphogenetic protein (BMP) signaling, activates SMAD2/3, which in turn induces the transcription of SNAI1 and GREM1, thereby establishing a self-sustaining autocrine loop that amplifies EMT. Disrupting this loop via stromal GREM1 deletion, epithelial ACVR1C knockdown, kinase inhibition, or a novel GREM1-blocking peptide targeting the GREM1–ACVR1C binding interface significantly impairs CRC metastasis in vivo. Remarkably, while stromal GREM1 is required to initiate this loop, epithelial-derived GREM1 is sufficient to maintain metastatic progression. Clinically, epithelial GREM1 or ACVR1C expression predicts aggressive disease and poor survival. CONCLUSIONS: Our findings define a paradigm wherein CRC cells hijack the stromal factor GREM1 to establish a tumor-autonomous GREM1–ACVR1C autocrine loop. This loop licenses signaling independence, drives sustained EMT, and represents a novel, actionable vulnerability in advanced CRC.
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