PVT1 (Plasmacytoma Variant Translocation 1), a long non-coding RNA (lncRNA), is a critical player in diverse biological processes, particularly cancer biology. This review comprehensively examines PVT1’s multifaceted rol...PVT1 (Plasmacytoma Variant Translocation 1), a long non-coding RNA (lncRNA), is a critical player in diverse biological processes, particularly cancer biology. This review comprehensively examines PVT1’s multifaceted roles and molecular mechanisms. We delve into its predominant oncogenic functions while highlighting notable exceptions, offering new perspectives on its biological diversity. A key focus is the subcellular localizations of PVT1 across various cancers – an aspect underexplored in previous reviews despite its significant impact on function and regulatory mechanisms. Detailed mechanistic insights include PVT1’s linear and circular isoforms acting as miRNA sponges, its encoding of miRNAs, the influence of 8q24 rearrangements, and its regulation of protein stability/activity, and transcription. Furthermore, we examine PVT1’s functional elements, illuminating unexplored structural and regulatory features. The clinical implications of PVT1 as a biomarker and therapeutic target in oncology are also discussed. By synthesizing existing knowledge and introducing previously less-explored facets, this review aims to provide a comprehensive and up-to-date resource on PVT1’s role in health and disease.
Colorectal cancer (CRC) remains a major global health burden, with therapeutic resistance accounting for the majority of treatment failures and cancer-related deaths. Cancer stem cells (CSCs), which possess intrinsic dru...Colorectal cancer (CRC) remains a major global health burden, with therapeutic resistance accounting for the majority of treatment failures and cancer-related deaths. Cancer stem cells (CSCs), which possess intrinsic drug tolerance and self-renewal capacity, drive both primary and acquired resistance. CSCs maintain drug tolerance through the activation of core signaling cascades, including Wnt/β-catenin, Notch, Hedgehog, PI3K/Akt, and MAPK/ERK pathways, as well as through epithelial-mesenchymal transition (EMT), enhanced DNA repair, and PD-1/PD-L1-mediated immune evasion. These molecular alterations transform the tumor microenvironment (TME) into a stemness-supportive, immunosuppressive niche, thereby promoting tumor recurrence and metastasis. Recent advances in CSCs-directed therapy include monoclonal antibodies targeting stem cell surface antigens, small-molecule inhibitors that disrupt self-renewal pathways, epigenetic agents that reprogram stemness, and immunotherapies aimed at reactivating anti-tumor immune surveillance. Emerging multi-drug regimens that combine CSCs-targeted agents with chemotherapy, pathway inhibitors, or immune checkpoint blockade exhibit synergistic efficacy by simultaneously disrupting multiple resistance mechanisms. Additionally, nanotechnology-based delivery systems further improve drug bioavailability and tumor specificity while reducing systemic toxicity. Despite notable progress, substantial challenges remain, including the pronounced heterogeneity of CSCs, activation of compensatory signaling pathways, and the lack of robust biomarkers for CSCs identification and therapeutic monitoring. Future research should prioritize integrative multi-omics approaches to delineate CSCs-specific vulnerabilities, the rational development of synergistic combination therapies, and the efficient clinical translation of CSCs-directed strategies. This review aims to describe the molecular mechanisms of CSCs-driven drug resistance in CRC, highlighting the current and emerging therapeutic strategies to guide the development of more effective, personalized interventions.
Lysine lactylation (Kla), first described in 2019, is an emerging post-translational modification that converts lactate availability into changes in chromatin state and protein function. In cancer, where glycolysis and m...Lysine lactylation (Kla), first described in 2019, is an emerging post-translational modification that converts lactate availability into changes in chromatin state and protein function. In cancer, where glycolysis and microenvironmental hypoxia often elevate lactate, lactylation has been linked to transcriptional reprogramming, immune modulation, cellular plasticity, and therapy resistance. Here, we synthesize current evidence across major organ systems to clarify how lactylation is generated, interpreted, and removed, and how it interacts with tumor metabolism and the tumor microenvironment. We summarize enzymatic and non-enzymatic routes to Kla formation, discuss candidate writers, erasers, and readers, and highlight recurring mechanistic patterns spanning histone and non-histone substrates, including regulation of immune-evasive signaling, ferroptosis susceptibility, DNA repair, and stress-adaptation programs. We also integrate translational considerations, outlining druggable nodes within lactate production and transport pathways and within acetyltransferase and deacylase systems, and discuss how lactylation measurements could support patient stratification, pharmacodynamic monitoring, and rational combination strategies. Finally, we identify key open questions that currently limit clinical translation, including site-level causality, cell-type and spatial attribution in patient tissues, assay specificity and quantitative stoichiometry, and the conditions under which lactylation promotes versus restrains tumor progression. Together, this framework aims to guide mechanistic studies and accelerate the development of clinically actionable lactylation-directed interventions.
Therapeutic target for triple-negative breast cancer (TNBC) brain metastases remains a critical unmet clinical challenge. The roles of PIWI-interacting RNAs (piRNAs) in driving brain metastasis are poorly understood, des...Therapeutic target for triple-negative breast cancer (TNBC) brain metastases remains a critical unmet clinical challenge. The roles of PIWI-interacting RNAs (piRNAs) in driving brain metastasis are poorly understood, despite their known dysregulation and oncogenic functions in cancer. Here, we identified piR-1170 as a clinically relevant driver of TNBC brain metastasis through multi-model validation. Analysis of the TNBC cohort from Sun Yat-sen University Cancer Center revealed significant piR-1170 upregulation in brain metastases correlating with poor patient survival. First, upstream analysis confirmed that hnRNPK binds to piR-1170 to maintain the piRNA's stability, thereby sustaining piR-1170 upregulation in TNBC. Then, Functional studies with metastasis models demonstrated the brain-specific metastatic activity of piR-1170, enhancing tumor cell adhesion to brain endothelia, vascular extravasation, and parenchymal invasion. Mechanistically, piR-1170 promotes WTAP expression to enhance m6A methylation of DGAT2 and CD274 transcripts, activating de novo lipid synthesis and PD-L1-driven immune suppression to promote tumor adaptation to lipid-scarce metastases and avoid immune surveillance. Our study defined the piR-1170-driven axis that operates through coordinated metabolic reprogramming and immunosuppression, thus revealing its potential as a therapeutic candidate for TNBC brain metastasis.
The Notch signaling pathway, an evolutionarily conserved mechanism governing cell-cell communication, plays a pivotal and multifaceted role in shaping the tumor microenvironment (TME). This review provides a comprehensiv...The Notch signaling pathway, an evolutionarily conserved mechanism governing cell-cell communication, plays a pivotal and multifaceted role in shaping the tumor microenvironment (TME). This review provides a comprehensive overview of the core components and signaling mechanisms of the Notch pathway, encompassing both canonical and non-canonical signaling cascades. It further examines the dual functionality of Notch in tumorigenesis, functioning as either an oncogene or a tumor suppressor. A central focus of this review is the detailed investigation of the molecular mechanisms through which Notch signaling modulates key cellular constituents of the TME. Recent advances are systematically summarized, with emphasis on the role of Notch in regulating immune cell differentiation and function, angiogenesis, modulating cancer-associated fibroblasts, and maintenance of cancer stem cells. To facilitate clinical translation, the review highlights emerging therapeutic strategies targeting the Notch pathway, including γ-secretase inhibitors and modulators, monoclonal antibodies against ligands and receptors, small molecule inhibitors, and combination therapies integrating immune checkpoint inhibitors, chimeric antigen receptor immune cell therapy, cancer vaccines, and oncolytic viruses. Collectively, this work offers a systematic synthesis of recent progress in understanding the diverse roles of Notch signaling within the TME, emphasizing the therapeutic potential of modulating Notch signaling to reprogram the TME and enhance anti-tumor immunity.
BACKGROUND: Osteosarcoma (OS) is the most prevalent primary cancer of the bone. Metastasis and chemoresistance are the major obstacles to the improvement of OS prognosis, in which N-methyladenosine (mA) modification play...BACKGROUND: Osteosarcoma (OS) is the most prevalent primary cancer of the bone. Metastasis and chemoresistance are the major obstacles to the improvement of OS prognosis, in which N-methyladenosine (mA) modification plays an important role, but the exact molecular mechanisms are still unclear. METHODS: MeRIP-seq and RNA-seq were conducted on OS and paired adjacent normal tissue samples, which determined CACNA1E as a key mA-modified molecule. In vitro and in vivo models were established to evaluate the function of CACNA1E on OS growth, metastasis, and methotrexate (MTX) resistance, and to explore the upstream regulators and downstream effectors of CACNA1E. RESULTS: CACNA1E exhibited notable mA hypermethylation and upregulated expression in OS than adjacent normal tissues. CACNA1E knockdown effectively hindered OS growth, lung metastasis, and MTX resistance. METTL3, an mA "writer" boosted the mRNA stability of CACNA1E through mA modification, and this process was recognized and enhanced by IGF2BP2, an mA "reader". WNT7B was identified as a downstream molecule of CACNA1E. CACNA1E facilitated OS progression and MTX resistance by enhancing the non-canonical Wnt/Ca signaling through transcriptionally activating WNT7B. Furthermore, a novel combination treatment of targeted inhibition of CACNA1E with MTX had a synergistic effect on suppressing OS progression. CONCLUSIONS: Collectively, our findings uncover that METTL3-mediated mA modification of CACNA1E contributes to OS progression and chemoresistance through enhancing WNT7B-mediated non-canonical Wnt/Ca signaling. Targeted inhibition of CACNA1E in combination with MTX may be a promising alternative therapeutic strategy for patients with MTX-resistant OS.
Ferroptosis is a regulated form of cell death driven by iron accumulation and lipid peroxidation. Since its recognition as a modality of regulated cell death, ferroptosis has attracted increasing attention in cancer rese...Ferroptosis is a regulated form of cell death driven by iron accumulation and lipid peroxidation. Since its recognition as a modality of regulated cell death, ferroptosis has attracted increasing attention in cancer research for its distinct metabolic and redox dependencies. Recent evidence suggests that ferroptosis arises from systems-level regulation integrating metabolic reprogramming, gene and RNA control, and inter-organelle communication, while simultaneously influencing immune remodeling and the tumor microenvironment. These processes collectively determine ferroptosis susceptibility and therapeutic response. Ferroptosis-related genes and pathways have also emerged as potential biomarkers for risk stratification, treatment prediction, and imaging-based assessment. Moreover, small-molecule inducers, targeted inhibitors, and delivery systems capable of modulating ferroptosis demonstrate translational potential to overcome therapeutic resistance across multiple malignancies, including pancreatic cancer. This review synthesizes recent mechanistic and translational advances, highlighting ferroptosis as a conceptual bridge between cellular metabolism and tumor therapy, and outlining perspectives for precision diagnostics and personalized interventions.
Ferroptosis is a non-apoptotic form of regulated cell death driven by iron dependent lipid peroxidation. It sits at the intersection of several hallmarks of metastatic cancer, including metabolic rewiring, membrane remod...Ferroptosis is a non-apoptotic form of regulated cell death driven by iron dependent lipid peroxidation. It sits at the intersection of several hallmarks of metastatic cancer, including metabolic rewiring, membrane remodeling, epithelial mesenchymal plasticity, immune editing, and adaptation to distant niches. In this review, we integrate biochemical mechanisms with single cell, spatial, and in vivo data to map how ferroptotic pressure changes as tumor cells invade, travel through vessels, extravasate, enter dormancy, and re-awaken to form overt metastases. We highlight that these dynamics are strongly shaped by organ context. Lymph and adipose rich environments buffer lipid peroxidation and favor survival. In contrast, blood circulation increases oxidative load, and brain and liver niches impose distinct constraints on redox balance, iron handling, and lipid repair. We then examine how ferroptosis interfaces with the immune system. Ferroptotic stress can increase tumor antigenicity and danger signaling and thereby promote antitumor responses. The same stress, however, can reprogram monocytes, macrophages, and neutrophils, drive neutrophil extracellular trap formation, and support lipid exchange that weakens effector T cell function. This dual behavior helps explain why ferroptosis can restrict dissemination in some settings yet fuel pro-metastatic inflammation in others. On this mechanistic background, we evaluate therapeutic strategies that aim to exploit ferroptosis related vulnerabilities. These include inhibition of cystine supply or lipid repair pathways, radiosensitization regimens that increase lipid peroxidation, diet drug combinations that rewire sulfur and lipid metabolism, and nanoplatforms that co-deliver ferroptosis triggers with photo or sonodynamic therapies. Clinically, ferroptosis programs are increasingly linked to metastatic organotropism, responses to radiotherapy and immunotherapy, and patient survival, and they are beginning to guide biomarker development and early translational trials. We also discuss practical barriers, such as niche specific resistance circuits, constraints imposed by drug delivery and toxicity, and the scarcity of robust patient level ferroptosis readouts. Methodological advances - including compartment resolved reporters, spatial lipidomics, and circulating signatures of lipid damage - may help address these gaps. Overall, viewing metastasis through the ferroptosis lens reveals actionable vulnerabilities and supports rational radio immunometabolic combinations aimed at durable control of metastatic disease.
BACKGROUND: Circular RNAs (circRNAs) contribute to gene expression regulation by interacting with splicing factors, a process that is often disrupted in cancers such as cutaneous melanoma (CM). METHODS: A circRNA microar...BACKGROUND: Circular RNAs (circRNAs) contribute to gene expression regulation by interacting with splicing factors, a process that is often disrupted in cancers such as cutaneous melanoma (CM). METHODS: A circRNA microarray analysis was performed to identify differentially expressed circRNAs. qRT‒PCR was conducted to confirm the expression of circROR1. CCK-8, colony formation, wound healing, and transwell assays were used to analyze proliferation, metastasis and apoptosis in CM cells. Xenograft models and IHC experiments were established to confirm the effects of circROR1 on tumor growth and metastasis in vivo. RNA sequencing and pull-down–MS experiments were performed to identify the mechanisms downstream of circROR1. Nuclear and cytoplasmic fractionation, along with FISH experiments, were conducted to determine the cellular localization of circROR1. To target circROR1 for CM treatment, we used a microfluidic strategy to develop FA-PEG(si-circ) nanoparticles for efficient siRNA delivery. RESULTS: In CM samples, circROR1 levels were positively correlated with HNRNPL levels and tumor metastasis but negatively correlated with FOXO4 protein levels. CircROR1 was prevalent in CM, and its upregulation increased the levels of factors involved in epithelial–mesenchymal transition, cell migration, and invasion. CircROR1 overexpression conferred resistance to PD-L1-antibody therapy in CM cells by downregulating PD-L1 expression. CircROR1 recruited HNRNPL, influencing its nuclear translocation, and further prevented intron retention in FOXO4 mRNA. In HNRNPL-overexpressing CM cells, circROR1 upregulation inhibited FOXO4α expression and promoted FOXO4ζ expression. Increased FOXO4α expression counteracted circROR1’s effects and suppressed metastatic behaviors. FA-PEG(si-circ) enhanced siRNA stability and efficiency, reducing CM cell lung colonization in vivo. CONCLUSION: This study identified circROR1 as an oncogenic circular RNA that plays a crucial role in tumor progression and metastasis. CircROR1-targeted nanotherapy is a promising option for the treatment of metastatic cancer.
Emerging evidence reveals that intratumoral microbial (ITM) communities within the tumor immune microenvironment (TIME) critically influence tumor progression and immunotherapy response. Studies have shown that resident...Emerging evidence reveals that intratumoral microbial (ITM) communities within the tumor immune microenvironment (TIME) critically influence tumor progression and immunotherapy response. Studies have shown that resident bacteria within tumors, such as Sphingobacterium multivorum, regulate the secretion of chemokines like CCL20 and CXCL8, promoting the infiltration of regulatory T cells (Tregs) and inhibiting the function of cytotoxic T cells (CD8 T cells)-thereby weakening the efficacy of immune checkpoint inhibitors. Additionally, microbial metabolites may serve as potential biomarkers for predicting sensitivity to immunotherapy. Concurrently, engineered bacteria (e.g., oncolytic mineralizing bacteria) demonstrate significant antitumor effects by activating innate immunity and enhancing antitumor-specific immune responses, providing new strategies to overcome immunotherapy resistance. These findings highlight the dual role of ITM in tumor immune evasion and immunotherapy sensitivity, laying an important theoretical foundation for developing novel immunotherapy strategies targeting tumoral microbiota metabolism.
Pancreatic cancer exhibits a heightened level of autophagy, which supports the survival of cancer cells within the malignant microenvironment. The THUMP domain-containing protein 3 (THUMPD3)/ tRNA Methyltransferase Activ...Pancreatic cancer exhibits a heightened level of autophagy, which supports the survival of cancer cells within the malignant microenvironment. The THUMP domain-containing protein 3 (THUMPD3)/ tRNA Methyltransferase Activator Subunit 11-2 (TRMT112) complex has been identified as a tRNA mG methyltransferase in mammalian cells, and its functional role remains largely unexplored in pancreatic cancer. In this study, we demonstrate that both THUMPD3 and TRMT112 are upregulated in pancreatic cancer and significantly correlate with poor prognosis for patients. Knockdown of THUMPD3/TRMT112 inhibited pancreatic cancer cell growth in vitro and in vivo. Additionally, THUMPD3/TRMT112 knockdown significantly reduced autophagic flux, suggesting a role for THUMPD3/TRMT112-mediated tRNA mG modification in promoting pancreatic cancer cell proliferation and maintaining autophagy. Mechanistically, THUMPD3/TRMT112 deficiency suppressed TFEB translation via impaired mG modification of tRNA, thereby inhibiting pancreatic cancer cell growth and autophagy. In summary, this study has unveiled the crucial role of the THUMPD3/TRMT112 mG tRNA methyltransferase complex in maintaining pancreatic cancer cell growth and autophagy, presenting a promising target for future precision medicine interventions.
Initially recognized for its role in digestion, the gut microbiota is now acknowledged as a critical regulator of the host immune system. It influences not only the initiation and progression of cancer but also key thera...Initially recognized for its role in digestion, the gut microbiota is now acknowledged as a critical regulator of the host immune system. It influences not only the initiation and progression of cancer but also key therapeutic mechanisms through metabolic reprogramming, production of virulence factors, and remodeling of the immune microenvironment. Despite significant advancements in patient outcomes attributed to novel multi-target inhibitors and immune checkpoint blockers, several clinical challenges persist, including therapy resistance, low response rates, and considerable toxicity. The increasing recognition of the role of microbiota in oncology has positioned its modulation as a pivotal strategy influencing the efficacy and overall success of treatment. This review summarizes how alterations in the gut microbiota influence tumorigenesis, shape immune responses, and mediate resistance to cancer therapies. This study also explores therapeutic strategies designed to modulate the microbiota by restoring ecological balance, enhancing anti-cancer immunity, or rectifying metabolic dysregulation to overcome therapy resistance and improve clinical outcomes. These approaches present a novel paradigm for addressing the challenge of drug resistance in cancer therapy.
Castellanet O, Monatte J, Corvaisier N
… +11 more, Kaoutari AE, Kaya M, Ferreira L, Audebert S, Camoin L, de Nonneville A, Gonçalves A, Borg JP, Michea P, Maina F, Lamballe F
BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous breast cancer subtype with limited treatment options. Predicting patient response to chemo-immunotherapy remains challenging, high...BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive and heterogeneous breast cancer subtype with limited treatment options. Predicting patient response to chemo-immunotherapy remains challenging, highlighting the need for robust stratification strategies. METHODS: We performed a multi-parametric analysis combining histological, genomic, transcriptomic, proteomic, and immune profiling in the immunocompetent MMTV-R26 TNBC mouse model and compared outcomes with patient data from human TNBC cohorts and TNBC tumor microarray. To enable therapeutic testing and functional validation, we established syngeneic grafts from primary tumors and used them to evaluate combined chemotherapy (epirubicin) and anti-PD-1 immunotherapy. RESULTS: Multi-parametric analysis of TNBC heterogeneity modeled by the MMTV-R26 mice identified four distinct TNBC clusters, defined by unique intrinsic (molecular/genomic) and extrinsic (immune) features, which closely parallel patient subtypes, including rare metaplastic forms, and correlate with clinical outcomes. Both intrinsic and immune hallmarks of primary tumors were conserved across serial syngeneic transplantations, confirming the translational value of this preclinical platform. Treatment assessments indicated cluster-specific therapeutic vulnerabilities associated with molecular and immune traits. Specifically, whereas chemo-immunotherapy is beneficial to neutrophil-enriched tumors, immunotherapy alone appears to be more effective in macrophage-enriched tumors. Our findings indicate that TNBC treatment response is shaped by the interplay between tumor-intrinsic and immune features. CONCLUSION: Our study provides a robust preclinical platform for precision immuno-oncology, enabling stratification of TNBC patients for tailored onco-immunotherapies.
BACKGROUND: Taxane-based chemotherapy is a main treatment modality for ovarian cancer and other solid tumors, but chemoresistance limits the clinical efficacy. Studies have shown tumor interaction with macrophages in the...BACKGROUND: Taxane-based chemotherapy is a main treatment modality for ovarian cancer and other solid tumors, but chemoresistance limits the clinical efficacy. Studies have shown tumor interaction with macrophages in the tumor microenvironment (TME) plays a significant role in taxane resistance, yet the underlying molecular mechanisms are poorly understood. METHODS: In this study, we employed translatome profiling of paclitaxel-treated cancer cells, live-cell imaging analysis, gene knockdown/knockout, and in vitro cancer-macrophage coculture assays to unravel a novel chemoresistance mechanism mediated by tumor-macrophage interaction via the NOTCH2-JAG1 axis. The in vitro data were further validated by multiple xenograft, syngeneic and patient-derived xenograft mouse tumor models of ovarian cancer as well as ovarian cancer patient samples. RESULTS: We found paclitaxel selectively induced translational upregulation of NOTCH2 via cytoplasmic polyadenylation, and this NOTCH2 upregulation persisted after mitotic exit. Subsequent NOTCH2 activation by JAG1 expressed mainly on the neighboring macrophages promoted tumor cell survival and simulated cytokine release, such as CSF1 and IL-1β, that recruited JAG1-expressing macrophages, thus forming a positive feedback loop that further enhanced the pro-tumor NOTCH2 activity. Genetic depletion or pharmacological inhibition of NOTCH2 with the γ-secretase inhibitor attenuated macrophage infiltration and sensitized tumor response to paclitaxel in multiple preclinical models of ovarian cancer. Moreover, single-cell RNA sequencing analysis identified a JAG1-high macrophage subset that was enriched by paclitaxel treatment and attenuated by NOTCH inhibition. Clinically, high NOTCH2 expression in ovarian tumors was associated with recurrence and shorter progression-free survival of ovarian cancer patients. CONCLUSIONS: Paclitaxel-induced translational upregulation of NOTCH2 enables immediate juxtacrine activation by JAG1-positive macrophages, coupling tumor cell survival with immune remodeling in the tumor microenvironment to drive chemoresistance. Our results suggest NOTCH2 is a viable biomarker for paclitaxel resistance and that combining NOTCH2 inhibitor with taxane is an effective therapeutic strategy to selectively disrupt tumor-macrophage interaction and overcome macrophage-mediated taxane resistance in NOTCH2-positive tumors.
Precision oncology has transformed cancer care by tailoring treatments to individual molecular profiles, but many patients still fail to benefit from current therapies. In this context, biomarkers, particularly those mea...Precision oncology has transformed cancer care by tailoring treatments to individual molecular profiles, but many patients still fail to benefit from current therapies. In this context, biomarkers, particularly those measurable in non-invasive liquid biopsies, offer a promising path toward more effective and dynamic therapeutic strategies. Traditionally, circulating tumor DNA (ctDNA) has guided therapeutic decisions, but its limitations in capturing tumor complexity are becoming increasingly apparent. Conversely, non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are emerging as powerful biomarkers due to their stability in all body fluids and their dynamic regulation in response to treatment. Encapsulated in extracellular vesicles (EVs) or associated with protein/lipid complexes, circulating ncRNAs are released by both tumor and microenvironmental cells, offering a unique biological insight. This review highlights the unique potential of ncRNAs as longitudinal biomarkers for monitoring therapeutic responses, detecting recurrence, and personalizing cancer management in real time, marking the beginning of a new era in precision oncology.
BACKGROUND: Small cell lung cancer (SCLC) remains a highly lethal malignancy with limited therapeutic options. The purpose of this study was to investigate the central role of histone deacetylase 6 (HDAC6) in SCLC progre...BACKGROUND: Small cell lung cancer (SCLC) remains a highly lethal malignancy with limited therapeutic options. The purpose of this study was to investigate the central role of histone deacetylase 6 (HDAC6) in SCLC progression and its regulatory mechanisms to identify novel therapeutic strategies. METHODS: Preclinical SCLC models were utilized alongside molecular, cellular, and immunological techniques to elucidate HDAC6's mechanistic functions. The deacetylation of S100A2 and its impact on downstream signaling were analyzed, compensatory responses to HDAC6 inhibition were assessed, and the efficacy of dual-target inhibition was evaluated. RESULTS: HDAC6 was found to deacetylate the calcium-binding protein S100A2 at lysine 27, thereby stabilizing TGF-β/SMAD signaling to promote epithelial-mesenchymal transition (EMT) and metastatic dissemination. Simultaneously, HDAC6 polarized macrophages toward tumor-promoting M2 phenotypes, fostering an immunosuppressive microenvironment. HDAC6 inhibition triggered compensatory CSF1R upregulation, revealing a resistance mechanism. Dual blockade of HDAC6 and CSF1R synergistically suppressed primary tumor growth and metastasis while reprogramming macrophages toward anti-tumor M1 states. SCLC patients with co-high expression of HDAC6 and CSF1R exhibited worse progression-free survival (PFS). CONCLUSION: This study defines the HDAC6-S100A2-TGF-β/SMAD and HDAC6-CSF1R-macrophage axes as actionable therapeutic vulnerabilities. The dual inhibition strategy provides a translational framework to overcome stromal and immune barriers in this recalcitrant cancer.
BACKGROUND: Interferons (IFNs) are key cytokines that drive immune responses against infections and cancer, yet few therapies have successfully leveraged IFN signaling for cancer treatment. Long noncoding RNAs (lncRNAs)...BACKGROUND: Interferons (IFNs) are key cytokines that drive immune responses against infections and cancer, yet few therapies have successfully leveraged IFN signaling for cancer treatment. Long noncoding RNAs (lncRNAs) are emerging as promising therapeutic candidates, but their roles in immune modulation remain largely unexplored. Here, we functionally characterize a breast cancer-associated lncRNA, BRRIAR, which primes the IFN signaling pathway in specific cancer contexts and represents a potential therapeutic strategy for estrogen receptor-positive (ER+) breast cancer. METHODS: BRRIAR expression and subcellular localization were examined using qPCR, in situ hybridization, single-cell RNA sequencing and spatial transcriptomics. BRRIAR target genes were identified through CRISPR interference, chromatin interaction assays and ChIP sequencing. Mechanistic studies in ER + breast cancer cells included CRISPR-Cas9 genome-wide screens, RNA sequencing, RNA pull-down followed by mass spectrometry, proliferation assays and Western blotting. The therapeutic potential of BRRIAR was evaluated via intratumoral delivery of lipid nanoparticle-encapsulated BRRIAR in ER + breast cancer xenograft models. Immune activation was assessed using flow cytometry and cytokine profiling of human peripheral blood mononuclear cells (PBMCs). RESULTS: We demonstrate that BRRIAR is a key target gene at the 3p26 breast cancer risk region. Primarily expressed in ER + breast tumors, BRRIAR acts both in cis and in trans. Nuclear BRRIAR regulates BHLHE40 expression in cis through chromatin interactions, while cytoplasmic BRRIAR binds in trans to the pattern recognition receptor RIG-I, priming IFN signaling. Overexpression of BRRIAR RNA triggers RIG-I signaling, inducing IFN responses, drives rapid, dose-dependent apoptosis of ER + breast cancer cells in vitro and in vivo, and promotes immune activation in human PBMCs. CONCLUSIONS: These findings establish lncRNAs as key regulators of tumor immunity and uncover a critical link between genetic risk, lncRNAs, cancer immunosurveillance and breast cancer development, positioning BRRIAR as a promising lncRNA-based RIG-I activator for ER + breast cancer therapy.
Hepatocellular carcinoma (HCC) is a common type of primary liver cancer and is considered the third leading cause of cancer-related deaths worldwide. The high aggressiveness and resistance to therapies exhibited by HCC p...Hepatocellular carcinoma (HCC) is a common type of primary liver cancer and is considered the third leading cause of cancer-related deaths worldwide. The high aggressiveness and resistance to therapies exhibited by HCC present significant challenges to global public health. As the primary metabolic organ in the human body, the liver undergoes substantial metabolic reprogramming during carcinogenesis, affecting various metabolic pathways including those involved in carbohydrates, lipids, and amino acids. Notably, disruptions in amino acid metabolism play a critical role in the initiation and progression of HCC, helping to sustain its malignant characteristics. This review aims to provide an in-depth analysis of the alterations observed in aromatic amino acids metabolism, branched chain amino acids (BCAAs) metabolism, glutamine metabolism, and other amino acid metabolism processes, including serine, arginine, and methionine, along with the expression patterns of associated metabolic enzymes. Furthermore, it discusses potential therapeutic approaches and their clinical relevance, offering insights and strategies for improving HCC diagnosis and treatment in the future.