Membrane proteins with nuclear localization often exert non-canonical functions. PTK7, an evolutionarily conserved pseudokinase and a prominent therapeutic target, is primarily recognized for its cell-surface signaling; however, its intracellular role in tumor biology remains unclear. Here, we identify a previously unrecognized role of PTK7 in coordinating DNA damage response and tumor immune response in triple-negative breast cancer (TNBC). Mechanistically, PTK7 translocates to the nucleus where it associates with DNA-dependent protein kinase (DNA-PKcs), acting as a molecular scaffold to enhance its kinase activation and facilitate non-homologous end-joining (NHEJ) repair. Loss of PTK7 impaired DNA-PKcs-associated non-homologous end-joining (NHEJ) repair, increased double-strand breaks, and subsequent activation of the STING-IFN axis. Furthermore, PTK7 deficiency significantly sensitizes TNBC tumors to anti-PD-1 therapy in vivo. Clinically, high PTK7 expression correlates with suppressed immune signatures and poor immunotherapy response in TNBC patients. Together, our findings uncover a PTK7-associated DNA repair and immune-evasion program in TNBC and nominate PTK7 as a potential biomarker and therapeutic target for improving immunotherapy response.

Cancer cell intravasation requires both directed invasion toward the vasculature and access to functional blood vessels that act as intravasation sites. Using intravital video microscopy, we identified the peptide hormone adrenomedullin 2 (ADM2) as a critical regulator of this process. ADM2 was selectively upregulated in a highly invasive subpopulation of cancer cells that localize near blood vessels and actively drive intravasation. Knockdown of ADM2 significantly impaired intratumoral cancer cell invasion and intravasation in a chicken embryo metastasis model and in vitro. ADM2-deficient tumors exhibited reduced vascularization, limiting the availability of competent intravasation sites. Moreover, loss of ADM2 suppressed the formation of invasive metastatic lesions, indicating a requirement for ADM2 at multiple stages of the metastatic cascade. Consistently, targeting ADM2 in a mouse metastasis model inhibited the development of large intratumoral blood vessels and reduced metastasis. Collectively, these findings establish ADM2 as a previously unrecognized regulator of tumor-vascular interactions and highlight its potential as a therapeutic target to simultaneously disrupt invasion, vascular support, and metastatic dissemination.

This study identifies the previously uncharacterised transmembrane protein SMCO2 as a broadly upregulated factor in multi-organ adenocarcinomas and defines it as a novel mitochondria-associated endoplasmic reticulum membrane (MAM) structural and signalling integrator. Adenocarcinoma cells maintain metabolic adaptability and resist cell death through enhanced mitochondrial-endoplasmic reticulum communication; however, the core transmembrane regulation node that regulates this process is still unclear. Our article proves that SMCO2 interacts with VDAC1, enhances its association with STAT3, and promotes mitochondrial localisation and S727 phosphorylation of STAT3. The SMCO2-driven VDAC1-STAT3 axis modulates mitochondrial Ca[2][+] signalling, oxidative stress homoeostasis, and pivotal ferroptosis-associated networks, ultimately conferring ferroptosis resistance on tumour cells. Targeting SMCO2 or the VDAC1/STAT3 pathway can effectively restore ferroptosis sensitivity. Overall, our study confirms that SMCO2 is a transmembrane regulatory factor and reveals that the MAM-STAT3 axis, as a new mechanism, links metabolic adaptation to adenocarcinoma cell death resistance and has potential therapeutic significance.

Dysregulation of histone demethylation is a pivotal epigenetic event driving malignant tumor progression. Thus, it is critical to understand the downstream signaling pathways that govern dysregulation of histone demethylation. Here, we identified KDM4A as the exclusively and significantly up-regulated member in testicular germ cell tumors (TGCTs) through a pan-family expression screen of histone demethylases (KDM1-8 and JMJD6) using the GEPIA database. KDM4A knockdown markedly inhibits TGCT cell migration and invasion in vitro, and metastatic potential in vivo. Mechanistically, KDM4A induces H3K9me3 demethylation at the CCL3 promoter, thereby restoring chromatin accessibility to facilitate STAT1-dependent CCL3 transcriptional activation, which activates the PI3K/AKT pathway, ultimately promoting focal adhesion turnover and enhancing cellular invasiveness. Furthermore, in a lung metastasis model, KDM4A significantly promoted distal colonization of TGCT in a CCL3-dependent manner. Summary, our findings reveal that KDM4A is a critical epigenetic regulator of TGCT metastasis, driving tumor progression via the STAT1-dependent CCL3 transcriptional activation, which promotes focal adhesion turnover by PI3K/AKT axis. Hence, targeting KDM4A may be a promising therapeutic strategy for improving the clinical prognosis of patients with metastatic TGCT.

Acquired resistance to oxaliplatin (Oxa) represents a major clinical challenge in the treatment of colorectal cancer (CRC). Lysosomes are intracellular degradative organelles that enable cancer cells to adapt to metabolic and environmental stress; however, their precise regulatory roles in drug resistance remain poorly understood. Here, we report that lysosomal damage and its selective autophagic clearance (lysophagy) occur frequently in both Oxa-treated CRC cells and Oxa-resistant (OxaR) CRC cells. Through quantitative proteomics, we identified the significant downregulation of mitochondrial transcription factor A (TFAM) as a key event in Oxa-treated and OxaR cells. Mechanistically, Oxa-induced TFAM loss leads to mitochondrial DNA (mtDNA) leakage into the cytosol, which activates the STING-TBK1 signaling axis. This pathway subsequently enhances lysophagic flux, providing cancer cells with a survival advantage under Oxa stress. Crucially, pharmacological inhibition of TBK1 abrogates this adaptive lysophagy, restoring Oxa sensitivity and suppressing tumor growth in both xenograft and patient-derived organoid models. Collectively, our study reveals a novel TFAM-mtDNA-STING-TBK1 signaling axis that promotes chemoresistance through the co-option of lysophagy, highlighting TBK1 as a viable therapeutic target to overcome Oxa resistance in CRC.

Resistance to PARP inhibitors (PARPi) remains a major clinical challenge in ovarian cancer (OC), emphasizing the need for novel strategies to enhance therapeutic efficiency. Our previous work revealed that the antimalarial drug quinacrine (QC) can be repurposed to induce cell death in OC by promoting lysosomal release of active cathepsin L (CTSL). Building on these outcomes, we investigated whether QC-activated CTSL influences DNA damage and homologous recombination (HR) repair in OC cells. Our experimental evidence shows that QC-activated CTSL downregulates key DNA repair proteins RAD51 and 53BP1, leading to impaired HR repair and increased DNA damage. Importantly, genetic knockdown of CTSL significantly reduced QC-induced DNA damage, confirming the CTSL plays a direct functional role in this process. We also found out that the response of combined QC and PARPi differs in models. CTSL was translocated to the nucleus (nCTSL) in responsive patient-derived ascitic (PDA) and patient-derived xenograft (PDX) spheroids. Contrarily, non-responsive models did not have nuclear CTSL. Mechanically, QC could not suppress CRM1/XPO1 nuclear export receptor in non-responsive cells, leading to continued export of CTSL from the nucleus. To address this, we have used the CRM1 inhibitor KPT-8602, which restored nuclear retention of CTSL. This led to enhanced therapeutic synergy with PARPi and overcame resistance in QC-treated PDA 3D-spheroids. Consistent with these findings, QC reduced tumor burden in both the cell-derived OVCAR-5 xenograft and PDX-PH070 models that showed QC-induced nCTSL, but not in the non-responsive PDX-PH095 model. However, in additional non-responsive PDX models (PH747 and PH081), treatment with QC and KPT-8602 substantially reduced tumor burden. Collectively, our results confirm a critical role for nuclear CTSL in QC-induced DNA damage and identify nCTSL as a possible predictive biomarker of therapeutic response. These results suggest that combining QC with PARPi or CRM1 inhibitors represents a promising strategy to overcome PARPi resistance in OC.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor prognosis, and the upstream regulatory mechanisms driving oncogenic signaling remain insufficiently defined. In this study, we identify a previously unrecognized nuclear function of the cytoskeletal protein ACTB in promoting ESCC progression. We show that ACTB translocates to the nucleus and directly binds to the promoter of the m6A reader gene YTHDC2, transcriptionally activating its expression. YTHDC2, in turn, binds to m6A-modified sites on AKT mRNA, preventing its degradation and enhancing its stability. This results in sustained activation of the PI3K-AKT-mTOR signaling pathway, a key oncogenic cascade that promotes tumor growth and survival. Integrated CUT&Tag and RNA-seq analyses revealed a direct ACTB-YTHDC2 transcriptional axis, while RNA immunoprecipitation and MeRIP-qPCR confirmed YTHDC2-AKT interaction via m6A recognition. Functional assays in ESCC cell lines, patient-derived organoids, and xenograft mouse models demonstrated that both ACTB and YTHDC2 are essential for ESCC proliferation and tumorigenicity. Notably, pharmacological inhibition of mTOR with rapamycin effectively suppressed ACTB-driven tumor phenotypes in vitro and in vivo, supporting the therapeutic relevance of this signaling axis. Together, our findings define a novel ACTB-YTHDC2-AKT-mTOR regulatory network that integrates transcriptional and epitranscriptomic control in ESCC. This study reveals a noncanonical nuclear role for ACTB and identifies a mechanistically tractable pathway that may be exploited for targeted therapy in ACTB-driven esophageal cancer.

Liver cancer exhibits limited and heterogeneous responses to immune checkpoint blockade, underscoring the need to elucidate tumour microenvironmental mechanisms sustaining immune dysfunction. Here, we integrated single-cell transcriptomic annotation with BayesPrism deconvolution across multiple bulk cohorts and combined these analyses with in vivo liver cancer models, functional assays, and mechanistic investigations to define tumour-associated neutrophil (TAN) programmes linked to clinical outcome. We identified a neutrophil subset characterized by elevated sphingolipid metabolism as the predominant poor-prognosis signature, with SPTLC2 serving as the key molecular marker. High SPTLC2 expression defining this sphingolipid metabolism-high neutrophil population correlated significantly with advanced disease stage, inferior overall survival, and increased tumour infiltration. Tumour cell co-culture induced SPTLC2 upregulation and enhanced sphingolipid metabolic activity in neutrophils. Functional assays verified that myriocin, an SPTLC2 inhibitor, suppressed the proliferation and metastasis of Liver cancer cells and remodelled the antitumour immune function of neutrophils. Myriocin attenuated neutrophil sphingolipid metabolism and restored ROS production and neutrophil extracellular trap (NETosis) formation, revealing a critical regulatory role for sphingolipid metabolism in neutrophil-mediated innate immunity, as corroborated by single-cell analyses showing impaired innate immune function in sphingolipid metabolism-high neutrophils. Mechanistically, we uncovered an SPTLC2-dependent sphingolipid-lipid raft checkpoint that remodels plasma membrane microdomains to constrain neutrophil anti-tumour effector functions. Specifically, myriocin restored NOX2-dependent ROS generation by reducing ceramide accumulation in lipid rafts, thereby facilitating p47[phox]-p22[phox] interaction and productive NOX2 complex assembly in tumour-conditioned neutrophils. Collectively, these findings reveal a previously unrecognized immunometabolic axis governing TAN dysfunction in liver cancer, establish SPTLC2 as a rational combinatorial target for cancer immunotherapy, and highlight the therapeutic potential of targeting sphingolipid metabolism to restore neutrophil-mediated antitumour immunity and restrain hepatocellular carcinoma progression.

Over the past decades, metastasis research has largely emphasized genetic and epigenetic regulators. Emerging evidence indicates that metabolites-including sugars (glucose, fructose), antioxidant vitamins, glutathione, lipids (palmitic acid, cholesterol), and amino acids (glutamine, aspartate, BCAAs)-can critically influence metastasis in a context-dependent manner by driving or restraining progression via metabolic reprogramming and signaling modulation. This review examines how cancer cells re-modulate core metabolic pathways to adapt and metastasize, summarizes how endogenous metabolites, dietary bioactive compounds, metabolic toxins, and pharmacological agents regulate metastasis, and discusses new concepts and perspectives on metabolic regulation of tumor metastasis, and outlines future directions in metabolite-driven tumor metastasis. The metabolic dependencies of metastasis provide a rational basis for intervention through integrated nutritional and therapeutic strategies.

N[6]-methyladenosine (m[6]A), the most prevalent internal RNA modification in mammals, regulates key cellular processes through writer, eraser, and reader proteins. Recent studies have emerged that dysregulation of m[6]A modifiers promotes tumorigenesis by altering RNA metabolism. However, the role of m[6]A in multiple myeloma (MM) remains enigmatic. Here, we identify YTHDC1, a nuclear m[6]A reader, as a key oncogenic factor in MM. YTHDC1 is upregulated in MM cells and associated with poor prognosis. Functional studies reveal that YTHDC1 facilitates MM cell growth and survival in an m[6]A-dependent manner. Mechanistically, YTHDC1 directly binds m[6]A-modified EP300 mRNA and enhances its stability and expression. In turn, p300 activates YTHDC1 transcription via H3K27ac deposition and IRF3/IRF4 recruitment, establishing a self-reinforcing feedback loop. This interplay between RNA m[6]A methylation and histone H3K27 acetylation contributes to MM pathogenesis. Our findings highlight the YTHDC1-EP300 axis as a promising target for therapeutic intervention.

Bone metastasis affects 30-40% of lung cancer patients, markedly reducing survival and quality of life, yet the underlying molecular mechanisms remain incompletely understood. Comparative transcriptomic profiling of primary lung tumors and paired bone metastases revealed pronounced KIFC1 enrichment in metastatic lesions, which correlated with poor bone metastasis-free survival. Functionally, KIFC1 enhanced lung cancer cell migration and adhesion toward osteoblast-like cells and upregulated the bone-homing factors CXCR4 and OPN. KIFC1 promoted osteoclast recruitment and differentiation while suppressing osteogenic differentiation, thereby disrupting bone homeostasis. Mechanistically, KIFC1 associated with RUNX2 through its C-terminal motor domain and promoted RUNX2 nuclear accumulation in a motor activity-, microtubule-, and importin-dependent manner. Nuclear RUNX2 directly activated TGFB1 transcription, resulting in preferential activation of the TGF-β/SMAD3 signaling pathway. Genetic silencing of RUNX2 or pharmacological inhibition of SMAD3 largely abrogated KIFC1-mediated pro-metastatic and pro-osteolytic effects. In vivo, KIFC1 knockdown reduced intraosseous tumor burden and alleviated trabecular bone loss, whereas KIFC1 overexpression exacerbated osteolytic lesions, which were mitigated by disrupting RUNX2/TGF-β/SMAD3 signaling. Collectively, our findings identify KIFC1-mediated RUNX2 nuclear transport as a previously unrecognized upstream regulatory mechanism that activates the TGF-β/SMAD3 axis during lung cancer bone metastasis, which provides a conceptual framework for the development of targeted therapeutic strategies.