The identification of novel therapeutic targets and agents to overcome chemoresistance remains a central challenge in triple-negative breast cancer (TNBC). Here, we report three key innovations: the discovery of a novel oncogenic circRNA, circPARPBP, as a driver of chemoresistance; the elucidation of its mechanism through the recruitment of the SRCAP complex to activate CCL20 transcription and cancer stemness; and the demonstration that the natural compound isoliquiritigenin (ISL) effectively suppresses this axis to overcome chemoresistance. TNBC is the most aggressive subtype of breast cancer with poor prognosis and limited treatment options. In this study, we identified circPARPBP, a circRNA (hsa_circ_0000432) derived from PARPBP gene, which was aberrantly upregulated in TNBC tissues and cells. Clinically, the upregulation of circPARPBP was notably associated with TNBC chemoresistance. In vitro and in vivo experiments demonstrated that circPARPBP promoted TNBC progression and chemoresistance. Mechanistically, circPARPBP recruited the SNF2-related CBP activator protein (SRCAP) complex to activate C-C motif chemokine ligand 20 (CCL20) transcription and thus contributed to cancer stemness and chemoresistance. ISL, a key bioactive substance extracted from licorice root, effectively suppressed the circPARPBP-SRCAP-CCL20 signaling pathway. Notably, patient-derived xenograft models demonstrated that ISL treatment effectively overcame TNBC chemoresistance, with a superior benefit when in combination with conventional chemotherapy. Collectively, our study identifies circPARPBP as a novel regulator of TNBC progression and chemoresistance via SRCAP-mediated CCL20 activation, and provides a preclinical rationale for the clinical development of ISL as a potential therapy targeting this axis.

AntiPD-1 immunotherapy improves survival in advanced hepatocellular carcinoma (HCC), but responses remain limited by the immunosuppressive, acidic tumor microenvironment (TME). We investigated whether intratumoral alkalization with sodium bicarbonate could enhance PD-1 blockade. Bicarbonate-induced intracellular alkalization disrupted mitochondrial membrane potential, triggered rupture, and activated the cGAS-STING pathway via cytosolic mitochondrial DNA release, while simultaneously inducing immunogenic cell death (ICD). In murine models, intratumoral bicarbonate recruited and activated dendritic cells and T cells, suppressing tumor growth and synergizing with antiPD-1 therapy. In a prospective clinical study (ChiCTR2100053537), 28 patients with advanced-stage and 2 with intermediate-stage HCC received Tislelizumab plus intratumoral 5% sodium bicarbonate. The objective response rate was 93.3% (CR 53.3%, PR 40.0%); median progression-free survival was 31 months, and median overall survival was not reached. Treatment was well tolerated. Biopsies revealed significantly increased CD3⁺, CD4⁺, and CD8⁺ T-cell infiltration with combination therapy versus Tislelizumab alone. In line with our previous work, through this mitochondria-centered mechanism bicarbonate links metabolic reprogramming with innate and adaptive immune activation. Thus, intratumoral bicarbonate functions as a safe and accessible immunometabolic adjuvant that markedly enhances PD-1 blockade efficacy in HCC.

Determining effective treatment strategies for prostate cancer patients with bone metastasis remains a difficult issue. Targeted engineered exosomes have the potential to deliver anticancer drugs to tumor sites in a highly efficient and precise manner while minimizing treatment-related side effects. Here, we assessed the function and value of targeted engineered exosomes loaded with circAKR1A1 (OE-circAKR1A1-exosomes) in bone metastatic prostate cancer cells. The function and underlying mechanism of OE-circAKR1A1-exosomes were investigated via in vivo and in vitro experiments. We observed a positive correlation between circAKR1A1 expression and prostate cancer metastasis and progression. Both in vivo and in vitro experiments confirmed that OE-circAKR1A1-exosomes specifically targeted prostate cancer cells in the bone microenvironment. This targeting mechanism activated the PI3K/Akt signalling pathway, thereby facilitating tumor invasion and metastasis. Collectively, our findings suggest that circAKR1A1 is a driver and treatment target for metastatic prostate cancer. Targeted delivery of therapeutic circRNAs via engineered exosomes represents a highly promising clinical therapeutic approach. The schematic diagram of this study E3 aptamer-modified engineered exosomes loaded with circAKR1A1 specifically target bone metastases in PCa, thereby activating the PI3K/Akt signalling pathway to facilitate tumor invasion and metastasis.

Colorectal carcinoma (CRC) remains a leading cause of cancer mortality, largely due to metastasis. Solid tumors, including CRC, must adapt to intratumoral hypoxia and oxidative stress, but the tumor-cell programs that couple these pressures to metastatic competence remain unclear. Across human CRC cohorts and cell lines, HIF-1α was coordinately upregulated and co-expressed with the metabolic effectors GLUT3 and fatty-acid synthase (FASN), most prominently in metastatic lesions. Using HIF-1α (HRE), SREBP1 (SRE), and NRF2 (ARE) transcriptional reporters, we identified HRE-high and SRE-high CRC subpopulations with enhanced clonogenicity and invasion that drove accelerated tumor growth and increased lung metastatic burden across multiple CRC models. Mechanistically, IGF1 and insulin signaling through IGF1R and AKT-mTOR increased HIF-1α and induced FASN and GLUT3, enabling lipogenic, glycolytic, and antioxidant programs to withstand hypoxic and oxidative stress. HIF-1α engaged an HRE-containing proximal region of the human FASN promoter independently of SREBP1. Stress assays revealed functional specialization: FASN promoted NRF2-associated antioxidant capacity and resistance to oxidative injury, whereas GLUT3 preferentially supported hypoxia tolerance. In vivo, lipid nanoparticle-encapsulated echinomycin rapidly suppressed HRE, SRE, and ARE activity, reduced peri-hypoxic induction of FASN and GLUT3, inhibited tumor growth, and eliminated lung metastasis. These findings define a growth factor-responsive, HIF-1α-centered stress-adaptive state and highlight HIF-1α transcriptional activity as a therapeutic target in metastatic CRC.

Prostate cancer (PCa) progression, particularly to castration-resistant prostate cancer (CRPC), is driven by androgen receptor (AR) reactivation and epigenetic alterations. Here, we identify lysine methyltransferase 2D (KMT2D) as a critical epigenetic oncogene in PCa. KMT2D expression is elevated in PCa and correlates with poor prognosis. Mechanistically, KMT2D facilitates AR signaling by recruiting the pioneer factor FOXA1 to AR-specific enhancers, promoting chromatin accessibility and activating AR target genes. FOXA1 mutations impair this regulation, demonstrating their functional interplay. Furthermore, KMT2D-FOXA1-AR axis modulates ketone body metabolism via transcriptional control of HMGCS2, supporting tumor growth. Pharmacological inhibition of UTX, a COMPASS complex demethylase essential for KMT2D function, disrupts H3K4me1 deposition and suppresses AR signaling and tumor proliferation. Altogether, we characterize KMT2D as a key driver of AR-dependent PCa progression and propose UTX inhibition as a promising therapeutic strategy.

Immune checkpoint blockade (ICB) remains ineffective in most colorectal cancers (CRC) due to intrinsic immune resistance. We identify guanylate-binding protein 2 (GBP2) as a key enhancer of ICB response through modulation of the gasdermin D (GSDMD)-Yes-associated protein (YAP) axis. Analyses of CRC cohorts, patient samples, organoids, and mouse models revealed that GBP2 directly binds GSDMD, inhibiting its cleavage-dependent activation and preventing YAP nuclear translocation. Activated GSDMD facilitates YAP nuclear accumulation, which represses CXCL9/10/11 transcription and limits CD8⁺ T-cell infiltration. Mechanistically, GBP2 disrupts this process by restraining non-pyroptotic GSDMD activity and maintaining YAP in its inactive cytoplasmic state. Genetic or pharmacologic inhibition of GSDMD restored YAP inactivation and sensitized tumors to anti-PD-L1 therapy. These findings define a GBP2-GSDMD-YAP signaling axis that inhibits immune evasion and represents a therapeutic target to overcome ICB resistance in CRC.

Chemotherapy resistance is a major factor contributing to the failure of nasopharyngeal carcinoma (NPC) treatment. Migrasomes can export damaged mitochondria out of the cell, and the timely removal of damaged mitochondria is key to cancer cell resistance. However, whether migrasomes regulate tumor resistance remains unknown. Here, we elucidated the role and mechanism of migrasomes in chemoresistance of NPC. We found that the formation of migrasomes was increased in cisplatin-resistant NPC cells, and inhibiting migrasome formation reduced cisplatin resistance. PinX1 was lowly expressed in tumor tissues of patients with high migrasome scores. Upstream mechanism analyses showed that TP53 was effectively bound to the promoter of PinX1, thereby enhancing its transcriptional activity. Knockdown of PinX1 facilitated migrasome formation via its telomerase inhibitory domain 252-328aa region binding to Rab11a, which relied on serine residues at the N-terminal 25aa site for promoting migrasome formation. Mechanistically, PinX1 recruited RanBP2 to induce the SUMOylation of Rab11a, leading to the degradation of Rab11a at the K207 site. Furthermore, PinX1 reduced cancer cell energy metabolism by inhibiting the export of damaged mitochondria via migrasomes. Collectively, TP53-activated PinX1 recruits RanBP2 to Rab11a, triggering Rab11a K207 SUMOylation and degradation, leading to impaired migrasome formation and mitochondrial transfer, and ultimately suppresses cisplatin resistance in NPC. Our study provides a new target for clinical reversal of chemotherapy resistance in patients with NPC.

Colorectal cancer (CRC) remains the third most common malignancy and a leading cause of cancer-related mortality worldwide. Despite immunotherapy advances, most CRCs respond poorly to immune checkpoint inhibitors due to their immunologically "cold" phenotype characterized by low immunogenicity and a suppressive tumor microenvironment. Oxidative stress has emerged as a critical determinant of antitumor immunity, with excessive reactive oxygen species (ROS) triggering immunogenic cell death, releasing tumor-associated antigens and damage-associated molecular patterns. However, endogenous mechanisms linking ROS regulation to innate immune activation remain incompletely understood. Here, we identify a previously unreported mitochondria-associated long non-coding RNA, lncRNA 606938, whose expression is inversely correlated with CRC progression. Mechanistically, lncRNA 606938 is exported from the nucleus via the HuR-IGF2BP2 complex and translocated to mitochondria through the mitochondrial targeting sequence and HMG2 domains of mitochondrial transcription factor A (TFAM). Within mitochondria, lncRNA 606938 enhances oxidative phosphorylation (OXPHOS) by upregulating mitochondrial DNA-encoded OXPHOS subunits, leading to excessive ROS production. In addition, lncRNA 606938 facilitates the recognition of N6-methyladenosine (m6A) sites on TFAM mRNA by IGF2BP2, thereby enhancing its stability and expression, further reinforcing mitochondrial oxidative stress. The elevated ROS induces mitochondrial damage and cytosolic release of mitochondrial DNA, which activates the cGAS-STING pathway and stimulates innate immune responses, ultimately suppressing tumor growth. Collectively, our findings highlight lncRNA 606938 as a novel upstream regulator of mitochondrial metabolism and innate immune activation, providing new insights into lncRNA-mediated reprogramming of the tumor immune microenvironment and uncovering a potential therapeutic strategy to sensitize CRC to immunotherapy.

Aggressive and therapy-resistant cancers present a significant challenge to treatment and are associated with poor patients' survival. Identifying molecular pathways and compounds that target these pathways is critical for improving patient outcomes. RNF4, an E3 Ubiquitin ligase, is pivotal for tumorigenesis in part by stabilizing oncoproteins and its role in DNA repair, thereby enhancing cancer cell survival and driving tumorigenesis. Elevated RNF4 levels are associated with poor prognosis in patients with carcinomas, melanoma, and sarcoma. Here, we describe the design and development of R4VPs, dual degrader compounds connecting two E3 ubiquitin ligases; Von Hippel-Lindau protein (VHL) with RNF4. R4VPs promote RNF4 degradation and thereby reduce the levels of its stabilized phosphorylated oncoproteins, while concomitantly eliminating VHL. R4VPs selectively induce ferroptotic cell death in cancer cells, sparing non-tumorigenic and primary cells in part by binding and modifying the anti-ferroptotic selanoproteins GPX4. R4VPs-induced ferroptosis preferentially targeting cells harboring tumor-driving mutations in the EGFR pathway, whereas it does not affect PI3K-transformed cells. As a consequence, R4VPs effectively induce cell death in Receptor Tyrosine Kinase inhibitor-resistant melanoma and primary patient sarcoma cells. Our findings highlight the potential of selective ferroptosis inducers, such as R4VPs, as a therapeutic strategy for hard-to-treat cancers.

Cancer-associated fibroblasts (CAFs) are necessary constituents of the tumor microenvironment, significantly promoting cancer cell proliferation, invasion, and therapeutic resistance through the secretion of various factors. This study elucidates a novel metabolic-epigenetic mechanism by which glutathione peroxidase 8-positive (GPX8⁺) CAFs confer lenvatinib resistance in hepatocellular carcinoma (HCC). We demonstrate that GPX8 overexpression in CAFs activates the PI3K/AKT/mTOR signaling pathway by suppressing endoplasmic reticulum stress, driving glycolytic reprogramming and lactate production. HCC cells import this CAF-derived lactate via monocarboxylate transporter 1 (MCT1), elevating histone H3 lysine 18 lactylation (H3K18la) levels. Increased H3K18la enrichment at the promoter of bromodomain and PHD finger-containing protein 1 (BRPF1) transcriptionally upregulates BRPF1 expression. Furthermore, we found that BRPF1 mediates lenvatinib resistance in HCC by promoting H3K14ac and inducing activation of the EGFR pathway. Pharmacological inhibition of MCT1 (AZD3965) or BRPF1 (GSK5959), effectively reversed lenvatinib resistance in vitro and in vivo. These findings establish the GPX8⁺ CAF/lactate/MCT1/H3K18la/BRPF1/EGFR axis as a pivotal driver of lenvatinib resistance and identify MCT1 and BRPF1 as actionable therapeutic targets for overcoming resistance in HCC.