Molecular Cancer[JOURNAL]
Sun
200 papers
Cuproptosis in inflammation and cancer: molecular mechanisms and therapeutic targets.
Liu J, Huang H, Luo P … +11 more , Shen Y, Hu S, Zhang X, Yu Q, Liu Y, Huang L, Luo J, Zhu Y, Zhao Q, Jiang D, Tang B
Mol Cancer · 2026 Mar · PMID 41888797 · Full text
Cellular processes depend on Copper(Cu) homeostasis, but overload of Cu in cells leads to the disruption of that balance and induces a specialized model of regulated cell death known as cuproptosis. As opposed to the con...
Cellular processes depend on Copper(Cu) homeostasis, but overload of Cu in cells leads to the disruption of that balance and induces a specialized model of regulated cell death known as cuproptosis. As opposed to the conventional cell death modalities, this mechanism features the connection of Cu ions with fatty-acylated elements of the TCA cycle, which subsequently promotes proteotoxic clustering and dysfunction of the mitochondria. Cuproptosis has a distinct and regulated pathway that is not responsive to standard cell demise inhibitors, which warrant its potential role in a number of pathophysiological mechanisms, specifically in the pathogenesis of inflammatory conditions and cancer. However, the disease-specific regulatory networks of its functioning cannot be comprehensively studied, and it has been a great challenge in regard to designing specific therapeutic developments. This paper critically analyzes the regulatory processes of copper equilibrium and cuproptosis, focusing on the important regulatory genes and their interaction networks. We describe pathological implications of cuproptosis in inflammation and malignancies, outline the recent intervention methods, and address the limitations of the current research such as lack of in vivo models and biomarkers. Not only do we offer a systematic source of information about biological importance of cuproptosis but also suggest novel knowledge about the specific treatment of inflammation and cancer which has a great theoretical value and promising opportunities of its practical implementation.
CAR-NK cell therapy for hematologic malignancies: advances, challenges and optimization strategies.
Liu W, Miao H, Weng L … +1 more , Cao X
Mol Cancer · 2026 Mar · PMID 41882710 · Full text
Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable efficacy in hematologic malignancies; however, its clinical application is limited by toxicities, such as cytokine release syndrome, immune eff...
Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable efficacy in hematologic malignancies; however, its clinical application is limited by toxicities, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and graft-versus-host disease. Natural killer (NK) cells, as key components of the innate immune system, can directly recognize and eliminate tumor cells without prior antigen sensitization. Capitalizing on their inherent allogeneic compatibility and potential for off-the-shelf use, chimeric antigen receptor NK (CAR-NK) cell therapy has emerged as a promising alternative to CAR-T strategies. Despite their potent antitumor activity in hematologic cancers, CAR-NK cells face several challenges: the need for optimized CAR designs, limited in vivo persistence and expansion, functional suppression by the immunosuppressive tumor microenvironment, as well as issues of antigen evasion, fratricide, host immune rejection, and scalable manufacturing. This review systematically summarizes recent advances in CAR-NK cell therapy for hematologic malignancies and outlines strategies to enhance its efficacy. These strategies include novel CAR designs, improved persistence and expansion, modulation of the immunosuppressive tumor microenvironment, and synergistic combination therapies. We also address the prevention of antigen evasion, fratricide, and host rejection—topics less comprehensively covered in prior reviews. Additionally, we examine the optimization of cell sources and manufacturing processes, with particular emphasis on emerging platforms for cell sorting and cryopreservation that have received limited attention. Furthermore, we discuss the current clinical landscape of CAR-NK cells and potential future strategies for optimizing clinical application. Together, these advances highlight the significant translational potential of CAR-NK cell therapy, a platform strengthened by its favorable safety profile and encouraging antitumor activity for treating hematologic malignancies.
SOS1: tracking the evolving path from promising to actionable therapeutic target in RAS-dependent cancers.
Luna-Ramírez L, García-Navas R, Santos E … +1 more , Baltanás FC
Mol Cancer · 2026 Mar · PMID 41882629 · Full text
SOS1 is a crucial guanine nucleotide exchange factor (GEF) that plays a key role in the activation of eukaryotic RAS GTPases, serving as a critical node in the highly conserved RAS/MAPK signaling pathway. Dysregulation o...
SOS1 is a crucial guanine nucleotide exchange factor (GEF) that plays a key role in the activation of eukaryotic RAS GTPases, serving as a critical node in the highly conserved RAS/MAPK signaling pathway. Dysregulation of the RAS-MAPK pathway, which is frequently driven by oncogenic RAS mutations, is implicated in approximately 30% of all human cancers, making it one of the most prevalent oncogenic drivers. As a direct activator positioned upstream of RAS, and in view of the quick appearance of resistance to a wide variety of recently developed allele-specific KRAS inhibitors, SOS1 constitutes a highly promising therapeutic target for a wide spectrum of RAS-driven malignancies, offering a strategy to inhibit oncogenic signaling independently of specific RAS mutations and to potentially help overcome resistance mechanisms associated with direct RAS inhibitors. Over the past three decades, a substantial body of preclinical evidence has accumulated regarding the potential of SOS1 as a therapeutic target. Focusing preferentially on data generated using patient-derived experimental contexts, we will provide in this review a comprehensive evaluation of a variety of recently developed small-molecule SOS1 inhibitory drugs and SOS1 degraders. Specifically, we describe here their specific therapeutic responses elicited in a variety of preclinical, in vitro and in vivo models involving different specific tumor types and cell lines harboring different oncogenic driver mutations. Furthermore, we highlight promising synergistic outcomes of the SOS1 inhibitors in combination with other RAS/MAPK pathway antagonists and discuss cases where SOS1 inhibition was reported to prevent or overcome resistance to current, FDA-approved RAS inhibitors. We also outline the clinical trials currently underway evaluating SOS1 inhibitors. Additionally, we explore the relatively underestimated potential of SOS2 as a therapeutic target, alongside the current state of development for SOS2 inhibitors. Finally, we address several underexplored clinical avenues regarding SOS1 inhibition for the treatment of specific cancer subtypes.
Multifunctional chitosan-doxorubicin nanocarriers: advancing targeted breast cancer chemotherapy.
Mishra G, Leharwani M, Alqahtani T … +5 more , Al Shmrany H, Gupta G, Sahebkar A, Patil UK, Kesharwani P
Mol Cancer · 2026 Mar · PMID 41872836 · Full text
Breast cancer remains one of the leading causes of cancer-related mortality worldwide, with chemotherapy continuing to play a central role in clinical management. Doxorubicin, despite its potent antitumor activity, suffe...
Breast cancer remains one of the leading causes of cancer-related mortality worldwide, with chemotherapy continuing to play a central role in clinical management. Doxorubicin, despite its potent antitumor activity, suffers from severe dose-limiting cardiotoxicity, poor tumor selectivity and the rapid emergence of multidrug resistance. Chitosan, a naturally derived biocompatible polysaccharide, has emerged as a versatile nanocarrier platform capable of addressing these limitations through intelligent design strategies. This review explores how chitosan-based doxorubicin nanoplatforms have been engineered to recognize cancer cell surface markers, respond to tumor-specific cues such as acidic pH and elevated glutathione, and deliver drug combinations that dismantle resistance mechanisms. We examine both systemic nanoparticulate systems and innovative localized depots including injectable gels, implantable matrices and even oral bacteria-assisted carriers that concentrate chemotherapy at the tumor site while sparing healthy tissues. By detailing the intracellular journey of these nanoplatforms from receptor binding to nuclear DNA damage and apoptosis induction, this review illuminates the molecular basis of their enhanced efficacy. Finally, we discuss the translational challenges and future directions needed to bring these promising chitosan nanomedicines from bench to bedside for improved breast cancer outcomes.
Biomarker-empowered precision navigation of CAR-T cell therapy.
Wang Y, Cheng W, Kang K … +3 more , Niu T, Zhao A, Wu Y
Mol Cancer · 2026 Mar · PMID 41866480 · Full text
Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of relapsed or refractory hematologic malignancies and continues to advance clinically. However, its broader application is hindered by he...
Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of relapsed or refractory hematologic malignancies and continues to advance clinically. However, its broader application is hindered by heterogeneous efficacy, limited response durability, antigen-negative relapse, and both acute and delayed toxicities. Biomarkers are therefore critical for predicting clinical outcomes, optimizing product design, refining patient selection, evaluating early responses, and monitoring toxicities. In this review, we summarize current biomarkers across key biological compartments that determine CAR-T efficacy and safety: host-derived factors including baseline inflammatory profiles, immune composition, and T-cell fitness; product-related features such as CAR structure, cellular subsets, metabolic state, expansion, and persistence; tumor-derived markers including antigen expression, genomic characteristics, minimal residual disease, circulating tumor DNA, and tumor microenvironment. We also outline biomarkers associated with major CAR-T-related toxicities. Finally, we discuss how high-parameter flow cytometry, single-cell multi-omics, extracellular vesicles, and novel CAR platforms are advancing biomarker development. Collectively, these findings support a shift from individual candidate markers toward integrated longitudinal frameworks to guide precision CAR-T therapy and further improve efficacy, durability, and safety.
Precision immunotherapy for head and neck cancer: therapeutic combinations, biomarker strategies, and translational challenges.
Okuyama K, Naruse T, Matsushita Y … +4 more , Fujimoto J, Yanamoto S, Lei YL, Hu J
Mol Cancer · 2026 Mar · PMID 41851770 · Full text
Immune checkpoint inhibitors (ICIs) have fundamentally altered the therapeutic paradigm for head and neck squamous cell carcinoma (HNSCC); however, durable clinical benefit remains limited to biologically defined patient...
Immune checkpoint inhibitors (ICIs) have fundamentally altered the therapeutic paradigm for head and neck squamous cell carcinoma (HNSCC); however, durable clinical benefit remains limited to biologically defined patient populations. These clinical limitations necessitate a shift away from empirical monotherapy toward precision-guided combination strategies that actively reprogram immune resistance. In this review, we integrate contemporary clinical and translational evidence regarding ICI-based combinations with radiotherapy (RT), chemotherapy, and emerging non-cytotoxic sensitization approaches, with particular emphasis on neoadjuvant and perioperative treatment settings. Central to these strategies is the dynamic remodeling of the tumor immune microenvironment (TIME), rather than simple amplification of immune activation. Recent studies demonstrate that immune-sensitizing interventions - including RT-induced immunogenic cell death, innate immune pathway activation, metabolic and microbiome modulation, and bioengineered drug delivery systems-can convert immunologically inert tumors into immune-interrogable tissues by restoring antigen presentation, spatial immune organization, and effector T-cell competence. Concurrently, integrative biomarker frameworks-encompassing PD-L1 expression, tumor mutational burden, tertiary lymphoid structures, tissue-resident memory T cells, and immune spatial organization-are redefining approaches to patient stratification and therapeutic sequencing. Despite compelling mechanistic rationale, clinical translation remains hindered by inadequate biomarker integration, heterogeneous clinical trial design, and discordance between biological endpoints and survival outcomes. Collectively, these advances delineate a transition from empiric combination therapy toward immune-centric precision immuno-oncology in HNSCC, underscoring the necessity for biomarker-driven trial design, longitudinal immune monitoring, and multidisciplinary collaboration to translate mechanistic synergy into durable clinical benefit.
Correction: Single-cell tumor heterogeneity landscape of hepatocellular carcinoma: unraveling the pro-metastatic subtype and its interaction loop with fibroblasts.
Guo DZ, Zhang X, Zhang SQ … +9 more , Zhang SY, Zhang XY, Yan JY, Dong SY, Zhu K, Yang XR, Fan J, Zhou J, Huang A
Mol Cancer · 2026 Mar · PMID 41845369 · Full text
Abstract loading — click title to view on PubMed.
ADAT2-mediated A-to-I tRNA modification promotes oncogenic translation and colorectal cancer progression and chemoresistance.
Cheng CH, Ji F, Shen J … +9 more , Jiao Y, Chen D, Yang H, Ye L, Tao R, Wei Q, Kang W, Yu J, Wong CC
Mol Cancer · 2026 Mar · PMID 41845367 · Full text
BACKGROUND: Adenosine-to-Inosine (A-to-I) modification is one of the most common transfer RNA (tRNA) modifications in humans. However, the role of A-to-I tRNA modification in colorectal cancer (CRC) remains poorly unders...
BACKGROUND: Adenosine-to-Inosine (A-to-I) modification is one of the most common transfer RNA (tRNA) modifications in humans. However, the role of A-to-I tRNA modification in colorectal cancer (CRC) remains poorly understood. METHODS: tRNA modification was profiled by LC-MS in paired CRC and adjacent normal tissues (N = 70). The clinical significance of adenosine deaminase tRNA specific 2 (ADAT2) was evaluated using in-house (N = 157) and TCGA cohorts (N = 283). The function of ADAT2 in CRC was determined in intestine-specific ADAT2 knockout mice. Mechanism of ADAT2 was assessed by integrated RNA-sequencing, tRNA-sequencing, and ribosome-sequencing analyses. RESULTS: Among 32 tRNA nucleotide modifications, A-to-I modification is the top enriched tRNA modification in CRC tumors compared to paired adjacent normal tissues (P < 0.001). Consistently, A-to-I modification enzyme ADAT2 is elevated in CRC and associated with poor patient survival in independent patient cohorts. Functionally, ADAT2 overexpression promotes malignant phenotypes in CRC cells and patient-derived CRC organoids, whereas ADAT2 knockout exerts opposite effects. Intestine-specific ADAT2 knockout mice showed attenuated colorectal tumorigenesis. Integrated sequencing identified that ADAT2 boosts translation efficiency of genes highly dependent on A-to-I codons, specifically enriched in WNT/β-catenin signaling. We revealed HDAC7 as a downstream target, whereby ADAT2 promotes HDAC7 translation in an A-to-I dependent fashion. HDAC7 interacts with β-catenin, leading to its activation and nuclear translocation. For translational value, ADAT2 promotes chemoresistance in CRC, and targeting ADAT2 by VNP-encapsulated ADAT2-siRNA promoted Oxaliplatin and 5-Fluorouracil efficacy to suppress CRC growth. CONCLUSIONS: ADAT2-driven tRNA A-to-I modification promotes CRC tumorigenesis and chemoresistance via HDAC7-WNT/β-catenin axis, and is an independent prognostic factor.
The pre-metastatic niche: mechanisms, heterogeneity, and therapeutic opportunities.
Zhang XR, Wei B, Jiang BH … +1 more , Ren WH
Mol Cancer · 2026 Mar · PMID 41845337 · Full text
Metastasis remains the leading cause of cancer-related mortality. The concept of the pre-metastatic niche (PMN) has provided a new framework for understanding how tumors establish favorable conditions in distant organs b...
Metastasis remains the leading cause of cancer-related mortality. The concept of the pre-metastatic niche (PMN) has provided a new framework for understanding how tumors establish favorable conditions in distant organs before metastatic colonization. This review delineates the cellular and molecular hallmarks of PMN, including immune suppression, vascular/lymphatic remodeling, metabolic reprogramming, and stromal reorganization, and traces their spatiotemporal evolution from initiation to colonization. It further examines the origins of metastatic lesions, with a focus on circulating tumor cells (CTCs) and stromal stem-like cells, highlights the pivotal role of extracellular vesicles (EVs) in mediating intercellular communication, metabolic reprogramming, and therapeutic applications. Deciphering the immune and stromal determinants of PMN formation offers key mechanistic insight into organ-specific metastasis. Consequently, this review explores translational strategies targeting the PMN, such as biomarker development, spatiotemporal profiling aided by artificial intelligence (AI), and immune, metabolic, or EV-based interventions. Deciphering PMN biology is therefore poised to open new avenues for the early interception and treatment of metastasis.
Targeting cholesterol-driven immunometabolism in cancer: from molecular circuits to clinical translation.
Ma Q, Chen B, Li T … +2 more , Lu Y, Li X
Mol Cancer · 2026 Mar · PMID 41840707 · Full text
Cholesterol integrates membrane organization, oncogenic signaling, and tumor immune regulation. Consistent with this central role, cholesterol homeostasis is frequently rewired in cancer, and dysregulated cholesterol met...
Cholesterol integrates membrane organization, oncogenic signaling, and tumor immune regulation. Consistent with this central role, cholesterol homeostasis is frequently rewired in cancer, and dysregulated cholesterol metabolism is increasingly recognized as a key contributor to tumor initiation and progression. Accumulating evidence indicates a mutually reinforcing interplay between oncogenic pathways and cholesterol metabolism: malignant transformation upregulates cholesterol biosynthesis and related homeostatic programs, and the ensuing metabolic reprogramming supports tumor growth, metastatic competence, and immune evasion. Beyond serving as structural components of cellular membranes in proliferating cells, cholesterol and its derivatives can act as signaling mediators that reshape membrane microdomains, reprogram oncogenic circuitry, and modulate stress-adaptation pathways in a context-dependent manner. Importantly, cholesterol metabolism is also remodeled in immune cells within the tumor microenvironment, where alterations in sterol flux and oxysterol signaling can influence antigen presentation, T-cell activation versus dysfunction, and myeloid polarization, thereby shaping responses to immunotherapy. Although cholesterol metabolism represents a promising therapeutic target, clinical translation of cholesterol-modulating agents remains limited. Key obstacles include the poor tumor specificity of current drugs (e.g., statins and cholesterol absorption inhibitors), cancer cell metabolic plasticity, and context-dependent tumor-immune interactions. Emerging next-generation strategies encompass enzymatic inhibitors, targeted delivery platforms, and gene-editing systems. While these approaches show promising preclinical results, their clinical translation demands systematic optimization, pharmacodynamic biomarker development, and patient stratification aligned with precision oncology principles. This review synthesizes mechanistic links between cholesterol-driven metabolic rewiring and cancer and critically appraises preclinical and clinical advances, including representative clinical trials combining cholesterol-lowering interventions with systemic anti-cancer therapies.
GPR183 potentiates CAR-T cell infiltration and antitumor immunity through a positive feedback loop involving the oxysterol 7α,25-OHC.
Guo R, Guo C, Qin S … +8 more , Lin Z, Tong J, Wang Y, Zhao Z, Zuo W, Gao Q, Tan Q, Ma J
Mol Cancer · 2026 Mar · PMID 41840629 · Full text
BACKGROUND: Insufficient T cell infiltration into solid tumors represents a major barrier to effective immunotherapy, particularly in the context of CAR-T therapy. Identifying key molecules capable of promoting T cell mi...
BACKGROUND: Insufficient T cell infiltration into solid tumors represents a major barrier to effective immunotherapy, particularly in the context of CAR-T therapy. Identifying key molecules capable of promoting T cell migration to tumor sites is therefore critical. GPR183 (EBI2), a receptor for oxidized sterols, has not yet been fully characterized in terms of its role in antitumor T cell immunity or its potential for application in CAR-T cell engineering. METHODS: Public single-cell transcriptomic data from breast cancer and ovarian cancer were analyzed to identify distinct expression patterns of GPR183 across T cell subsets, which were validated using flow cytometry. Functional assays, including in vitro Transwell migration experiments, as well as GPR183 knockout and overexpression models, demonstrated that GPR183 regulates T cell migration. To investigate the underlying molecular mechanisms, we employed ligand stimulation, co-culture systems, and transcriptome sequencing. Furthermore, we generated HER2-targeted CAR-T cell models with either GPR183 knockdown or overexpression, and systematically evaluated the impact of GPR183 on CAR-T cell function through in vitro cytotoxicity assays, IFN-γ secretion measurements, and in vivo tumor xenograft models in mice. RESULTS: Single-cell analysis revealed that GPR183high T cells exhibit a central memory phenotype and are enriched in migration-related signaling pathways. Functional experiments confirmed that GPR183 acts as a key positive regulator of T cell migration. Mechanistically, direct contact between T cells and tumor cells induced upregulation of CH25H and CYP7B1 in tumor cells, leading to increased production of 7α,25-OHC, which activated GPR183 and further enhanced its expression, establishing a positive feedback loop. In the HER2-CAR-T model, GPR183 overexpression significantly enhanced tumor infiltration, IFN-γ secretion, and tumor cell killing, and resulted in an additively improved antitumor efficacy in vivo. CONCLUSION: This study reveals, for the first time, that the GPR183-mediated positive feedback loop is a critical novel mechanism governing T cell tumor infiltration. Enhancing GPR183 expression through genetic engineering represents a promising strategy that significantly improves the migratory capacity and antitumor functionality of CAR-T cells, thereby providing a new therapeutic target and theoretical foundation for overcoming current limitations in the treatment of solid tumors.
Targeting MYC in T-Cell lymphoma via epigenetic modulation with a small-molecule inhibitor.
Liu B, Jiang B, Liu S … +14 more , Zhang S, Huang Z, Zhang M, Zhao X, Li Q, Li X, Xia J, Huang D, Li H, Luo X, Ma N, Hu Y, Zhang X, Rao J
Mol Cancer · 2026 Mar · PMID 41826982 · Full text
T-cell lymphoma (TCL) represents a heterogeneous group of highly aggressive malignancies with poor clinical outcomes because of limited therapeutic options. Hence, targeted therapeutic strategies for TCL are urgently nee...
T-cell lymphoma (TCL) represents a heterogeneous group of highly aggressive malignancies with poor clinical outcomes because of limited therapeutic options. Hence, targeted therapeutic strategies for TCL are urgently needed. Up-regulation of MYC is observed in more than 90% of all patients with TCL and correlates with tumor progression. Thus, targeting MYC may be an attractive therapeutic strategy for TCL. Here, we identified Lanatoside C (LATC) as a potent anti-TCL agent through unbiased high-throughput screening using an FDA-approved drug library. LATC inhibited cell proliferation and invasiveness of TCL in both the tumor-bearing mice and preclinical PDX models. Mechanistically, LATC disturbed the interaction between m5C reader YBX1 and m5C-modified MYC mRNA to reduce MYC mRNA stability through binding and blocking the RNA recognition domain of YBX1. Meanwhile, LATC directly targeted oncogenic p300 to enhance its proteasomal degradation through repressing UCHL3-mediated p300 deubiquitylation, which consequently down-regulated H4K16 lactylation in the MYC promoter to inhibit its transcription. Taken together, we identified LATC as an epigenetic agent by dually targeting post-transcriptional YBX1/MYC mRNA stability and transcriptional p300/H4K16 lactylation to inhibit MYC-driven T-cell lymphoma progression, providing a novel targeted therapeutic strategy for patients with MYC overexpression.
Context-dependent effect of glucocorticoid receptor activity shapes ovarian cancer cell plasticity and therapy response.
De Girolamo M, Ibello E, Improda T … +13 more , Tedesco I, Dell'Aversana C, Buonaiuto S, Arbucci S, D'Aniello C, De Cesare D, Franco R, Ambrosino C, Altucci L, Cobellis L, Patriarca EJ, Minchiotti G, Cobellis G
Mol Cancer · 2026 Mar · PMID 41821050 · Full text
BACKGROUND: The glucocorticoid receptor (GR) has been implicated in tumor progression and therapy resistance, yet its role in ovarian cancer (OC) remains controversial. In particular, how GR integrates environmental cues...
BACKGROUND: The glucocorticoid receptor (GR) has been implicated in tumor progression and therapy resistance, yet its role in ovarian cancer (OC) remains controversial. In particular, how GR integrates environmental cues to control OC plasticity and therapeutic responses is poorly understood. METHODS: We investigated GR function in ovarian cancer (OC) cells by integrating genetic and pharmacological approaches. By using both OC cell lines and patient-derived cells, we performed a comprehensive set of phenotypic, molecular and functional assays alongside genome-wide transcriptomic analyses. We also extended these analyses to physiologically relevant 3D systems, including tumor spheroids and organotypic cultures, to better recapitulate the in vivo tumor microenvironment. RESULTS: We provided unprecedented evidence that GR modulates OC behavior in a context-dependent manner. Under 2D culture conditions, GR enhanced cellular heterogeneity, epithelial–mesenchymal transition and migration, thereby increasing cisplatin resistance. Conversely, in a 3D context, GR exerted a marked yet reversible antiproliferative effect, characterized by reduced protein synthesis and adaptative stress responses. Mechanistically, GR activity converged on inhibition of glycolysis and activation of gluconeogenesis. Indeed, pharmacological inhibition of glycolysis with 2-deoxyglucose phenocopied GR-induced mesenchymalization in 2D cultures and growth inhibition in 3D models. Moreover, inhibition of gluconeogenesis with metformin prevented the GR-dependent antiproliferative effect in 3D models. Consistently, the glucocorticoid budesonide further potentiates the anti-proliferative effects of GR in OC spheroids. Transcriptomic analyses revealed that GR regulates gene programs involved in extracellular matrix organization and cell adhesion, uncovering a previously unrecognized role for GR in tumor microenvironment remodeling. CONCLUSIONS: Our findings reveal distinct, context-dependent effect of GR in OC cells, whereby GR activation promotes chemoresistance and migratory behavior in 2D cultures, while inducing a reversible slow proliferative state under 3D conditions. These results underscore the importance of cellular context in interpreting GR activity and suggest that selective GR modulators, including budesonide, may offer new therapeutic avenues for treating advanced-stage OC.
The multifaceted functions of selective autophagy in cancer: molecular basis, consequences, and clinical prospects.
Jiang M, Zhang K, Li M … +17 more , Tian Y, Wang T, Rodríguez RA, Lin Z, Meng J, Li C, Wang Z, Wu S, Cai Y, Zhang W, Guo R, Liu Y, Bai Y, Lai G, Zhang C, Bo Z, Wei R
Mol Cancer · 2026 Mar · PMID 41820985 · Full text
Selective autophagy is a critical cellular process in eukaryotic cells, characterized by the targeted degradation of specific organelles and proteins. This intricate mechanism plays a vital role in maintaining cellular h...
Selective autophagy is a critical cellular process in eukaryotic cells, characterized by the targeted degradation of specific organelles and proteins. This intricate mechanism plays a vital role in maintaining cellular homeostasis and has significant implications in the pathogenesis and progression of various diseases, notably cancer. Recent studies have highlighted the dual role of selective autophagy in cancer, acting both as a suppressor in the early stages and potentially facilitating progression in later stages. The complexity of selective autophagy, particularly in the context of oncogenesis, presents unique challenges. This review focuses on the molecular mechanisms underlying selective autophagy, its impact on cancer development and progression, and the challenges in leveraging this process for therapeutic interventions. We discuss the interplay between autophagy and cancer, examining how alterations in autophagic pathways contribute to tumorigenesis and the resistance of cancer cells to therapy. Additionally, we explore the potential of targeting selective autophagy pathways as a novel approach in cancer treatment, considering the challenges and prospects of such strategies.
Transcriptional networks weaving natural killer anti-tumor immune response.
Redavid AR, Bigliardi M, Ciarrocchi A … +1 more , Reggiani F
Mol Cancer · 2026 Mar · PMID 41814366 · Full text
BACKGROUND: Natural killer cells (NKs) are critical effectors of innate immune surveillance, capable of eliminating target cells without prior antigen sensitization. The crucial role of NKs in cancer immunity has largely...
BACKGROUND: Natural killer cells (NKs) are critical effectors of innate immune surveillance, capable of eliminating target cells without prior antigen sensitization. The crucial role of NKs in cancer immunity has largely been highlighted in both hematological and solid tumors. Besides, NK-based cell therapies have gained momentum as a compelling alternative to T cell-based approaches, due to their off-the-shelf availability and lower risk of toxicity. Still, the intrinsic molecular mechanisms driving NK anti-tumor efficacy in different tumor contexts are poorly described, drastically impairing their clinical exploitation. AIMS: This review aims to provide a comprehensive overview of the transcriptional networks defining each step of NK anti-tumor response, from tissue recruitment to target recognition and cytotoxic activation. The molecular mechanisms triggering NK dysfunction in the tumor microenvironment are also highlighted from a transcriptional perspective. The described time- and context-dependent transcriptional machinery is characterized by a constant interplay between activators and repressors, which integrates and balances signals deriving from the surrounding tumor ecosystem. CONCLUSIONS: Considering the relevance of transcription factors in controlling NK functions, their potential exploitation as novel therapeutic targets, through either pharmacological approaches or genome editing, is a new opportunity for cancer treatment.
Targeting circGDI2 disrupt HNRNPC-mediated mPORCN stabilization and enhance LGK-974 anti-tumor therapy in hepatocellular carcinoma.
Huang Y, Xu L, Yang L … +8 more , Wu Z, Li L, Dai Y, Dai J, Zhang M, Yi P, Jiang L, Xu M
Mol Cancer · 2026 Mar · PMID 41808165 · Full text
BACKGROUND: The functions of circRNAs in hepatocellular carcinoma (HCC) till needs to be further elucidated. METHODS: We assessed the biological functions of circGDI2 in vitro and in vivo by gain or loss of function expe...
BACKGROUND: The functions of circRNAs in hepatocellular carcinoma (HCC) till needs to be further elucidated. METHODS: We assessed the biological functions of circGDI2 in vitro and in vivo by gain or loss of function experiments. Then, fuorescence in situ hybridization (FISH), immunofluorescence (IF), RNA pull-down, mass spectrometry, and RNA immunoprecipitation (RIP) were applied to explore the interaction between circGDI2 and heterogeneous nuclear ribonucleoprotein C (HNRNPC). Finally, in vitro and in vivo experiments were performed to explore the influence of circGDI2 on the anti-tumor activity of LGK-974, a porcupine O-acyltransferase (PORCN) inhibitor. RESULTS: CircGDI2 was significantly overexpressed in HBV-related HCC, and its high expression was significantly associated with the growth and invasion characteristics of HCC. Functional experiments indicated that circGDI2 promoted the proliferation and metastasis of HCC cells both in vitro and in vivo. Mechanistic investigations revealed that circGDI2 physically binds to HNRNPC, facilitating its interaction with mPORCN, which stabilizes mRNA and promotes PORCN expression, thereby activating the Wnt signaling pathway and driving tumor proliferation and metastasis. Additionally, we found that the PORCN inhibitor LGK-974 effectively suppressed the proliferation and metastasis of HCC cells both in vitro and in vivo, and a series of experiments demonstrated that knocking down circGDI2 could enhance the antitumor effect of LGK-974, thereby maximizing the inhibition of HCC. CONCLUSION: CircGDI2 played a crucial role in the progression of HCC by interacting with HNRNPC to promote the Wnt signaling pathway. Meanwhile, LGK-974 can effectively inhibit HCC and targeting circGDI2 can enhance the antitumor effect of LGK-974.
CircNSD2 promotes metastasis and immune escape by increasing the USP10/SRSF6-mediated alternative splicing of TPM1 in TNBC.
Sun Y, Li Y, Niu T … +11 more , Wang Z, Yang J, He Y, Liang Y, Chen X, Chen T, Wang L, Chen B, Zhao W, Kong X, Yang Q
Mol Cancer · 2026 Mar · PMID 41808072 · Full text
BACKGROUND: Triple-negative breast cancer (TNBC) is the most malignant BC subtype, and metastasis remains the major cause of poor prognosis. TGF-β plays crucial roles in TNBC metastasis, yet the underlying mechanisms rem...
BACKGROUND: Triple-negative breast cancer (TNBC) is the most malignant BC subtype, and metastasis remains the major cause of poor prognosis. TGF-β plays crucial roles in TNBC metastasis, yet the underlying mechanisms remain unclear. Circular RNAs (circRNAs) are a novel type of regulatory RNA characterized by high evolutionary conservation and stability. This study aims to investigate the roles and mechanisms of circRNAs in TGF-β-induced TNBC metastasis. METHODS: CircNSD2 was detected in TNBC cells through high-throughput RNA sequencing. Gain- and loss-of-function assays were performed to evaluate the role of circNSD2. Chromatin immunoprecipitation (ChIP) and luciferase assays verified the regulatory effects of TGF-β on circNSD2. RNA pulldown, proteomic analyses, and RNA immunoprecipitation were conducted to identify the downstream targets of circNSD2. RESULTS: CircNSD2 expression was upregulated in patients with metastatic TNBC and correlated with an unfavorable prognosis. In vitro and in vivo studies indicated that circNSD2 facilitates TGF-β-induced TNBC metastasis and EMT. Mechanistically, circNSD2 is activated by TGF-β and cyclized by KHSRP. Moreover, circNSD2 functions as a scaffold to enhance the interaction between the SRSF6 and USP10 proteins, thereby preventing K48-linked polyubiquitination of SRSF6 at lysine 16 and inhibiting its proteasomal degradation. Furthermore, stabilized SRSF6 reprogrammed TPM1 alternative splicing, which resulted in TNBC metastasis. In addition, circNSD2 promoted immune escape in TNBC by upregulating PD-L1 expression and suppressing the antitumor immunity of CD8+ T cells. CONCLUSION: Our study revealed that circNSD2 increased TNBC metastasis and immune escape by promoting the USP10/SRSF6/TPM1 axis and that circNSD2 could serve as a potential diagnostic biomarker and therapeutic target for TNBC patients.
Retraction Note: Reduced expression of AMPK-β1 during tumor progression enhances the oncogenic capacity of advanced ovarian cancer.
Li C, Liu VW, Chiu PM … +3 more , Yao KM, Ngan HY, Chan DW
Mol Cancer · 2026 Mar · PMID 41808068 · Full text
Abstract loading — click title to view on PubMed.
Low-dose radiotherapy remodels the tumor immune microenvironment via the cGAS-STING pathway: mechanisms, challenges, and combination therapy strategies.
He Y, Zeng X, Liu Q … +8 more , Zhou L, Tang Y, Liu S, Wang X, Shen S, Ji J, Liu Z, Li J
Mol Cancer · 2026 Mar · PMID 41803899 · Full text
Low-dose radiotherapy (LDRT) has emerged as a promising immunomodulatory strategy by activating the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS-STING) pathway, thereby reprogramming the tumor immune micr...
Low-dose radiotherapy (LDRT) has emerged as a promising immunomodulatory strategy by activating the cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS-STING) pathway, thereby reprogramming the tumor immune microenvironment (TIME). LDRT induces DNA damage and cytosolic dsDNA accumulation, leading to cGAS-STING activation and subsequent production of type I interferon and proinflammatory cytokines. Consequently, LDRT promotes dendritic cell maturation, enhances CD8⁺ T cell infiltration and cytotoxicity, repolarizes macrophages toward an anti-tumor, immunostimulatory phenotype, and suppresses myeloid-derived suppressor cells and regulatory T cells (Tregs). However, sustained cGAS–STING activation may paradoxically induce immunosuppression through PD-L1 upregulation, T cell exhaustion, and enrichment of inhibitory cells. Combining LDRT with immune checkpoint inhibitors, STING agonists, chemotherapy, or CAR-T cell therapy synergistically amplifies antitumor immunity by overcoming TIME suppression and fostering long-term immune memory. Challenges such as radiotherapy heterogeneity, dose optimization, and STING pathway mutations require precise strategies including image-guided radiotherapy, nanocarrier-based delivery, and biomarker-driven patient stratification. This review highlights the dual role of LDRT-mediated cGAS–STING signaling in TIME remodeling and provides a foundation for developing novel combinatorial immunotherapies.
Inhibition of PRMT5 triggers synthetic lethality in ARID1A-deficient endometrial cancer by promoting aberrant R-loop accumulation.
Shu W, Dong K, Shen X … +9 more , Zhou X, Zhang J, Yu S, Cheng S, Zhang T, Chen G, Zhong G, Zhang J, Wang H
Mol Cancer · 2026 Mar · PMID 41803859 · Full text
BACKGROUND: Endometrial cancer (EC) is a common malignancy of the female reproductive system. The 5-year survival rate for advanced-stage EC patients is less than 20%, highlighting an urgent need for novel therapeutic st...
BACKGROUND: Endometrial cancer (EC) is a common malignancy of the female reproductive system. The 5-year survival rate for advanced-stage EC patients is less than 20%, highlighting an urgent need for novel therapeutic strategies. ARID1A, a key subunit of the SWI/SNF chromatin remodeling complex, is one of the most frequently mutated genes in EC, presenting a potential avenue for synthetic lethal targeting of ARID1A-deficient EC. This study aims to identify novel synthetic lethal targets for ARID1A-deficient EC and to elucidate the underlying molecular mechanisms, thereby providing new insights for clinical treatment. METHODS: The PRMT5 inhibitor JNJ-64,619,178 was identified via high-throughput compound screening as effectively inducing synthetic lethality in ARID1A-deficient EC cells. RNA-seq, comet assays, immunofluorescence, and Dot-blot experiments were employed to investigate DNA damage and R-loop accumulation. IP-MS, Co-IP, and proximity ligation (PLA) assays were used to detect interactions within the PRMT5-DHX9-R-loop axis. Chromatin immunoprecipitation‒PCR (ChIP‒PCR) experiments and dual luciferase reporter assays were performed to confirm that ARID1A directly transcriptionally regulates PRMT5. The synthetic lethal effect between PRMT5 inhibition and ARID1A loss was further validated using EC xenograft mouse models and patient-derived organoid models (PDOs). RESULTS: In this study, based on high-throughput drug screening, we identified that the PRMT5 inhibitor JNJ-64,619,178 exerts a significant synthetic lethal effect on ARID1A-deficient EC. PRMT5 inhibition promoted DNA damage, apoptosis, and R-loop accumulation in ARID1A-deficient EC. This synthetic lethality was confirmed in EC mouse models and PDOs. Mechanistically, we identified an association between ARID1A, PRMT5, and DHX9. Mechanistically, ARID1A directly binds the PRMT5 promoter and regulates its expression. ARID1A loss downregulates PRMT5, impairing arginine methylation and R-loop recruitment of DHX9—a key factor in R-loop resolution. Consequently, ARID1A-deficient EC cells become dependent on residual PRMT5 activity to maintain R-loop homeostasis. Inhibition of PRMT5 exacerbates R-loop accumulation and DNA damage, leading to synthetic lethality. CONCLUSION: This study identifies a novel synthetic lethal strategy for ARID1A-deficient EC, demonstrating that the PRMT5 inhibitor JNJ-64,619,178 acts by disrupting R-loop homeostasis. Our findings highlight the critical role of the ARID1A-PRMT5-DHX9 axis in tumor progression, thereby providing a novel molecular target and theoretical foundation for the precision treatment of ARID1A-deficient EC.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe