Microbial contributions to prostate health and disease extend beyond the mere detection of organisms in urine or tissue. Rather than acting as stable colonisers, microbial influences on the prostate are better conceptualised as converging fluxes: systemically circulating gut-derived metabolites, immune education occurring in distal lymphoid compartments, and intermittent exposure to microbial products from the lower urinary tract. These inputs converge on a limited set of conserved mediator-receptor axes-including short-chain fatty acids, bile acids and indole derivatives-that calibrate epithelial barrier integrity, inflammatory thresholds, antigen-presentation capacity and myeloid cell fate. Crucially, the biological relevance of these axes is stage-dependent. In benign prostatic hyperplasia and chronic prostatitis/chronic pelvic pain syndrome, metabolite tone shapes inflammatory activation thresholds and barrier resilience. In localized prostate cancer, these same pathways intersect with antigen-processing machinery and immune exclusion. In castration-resistant disease, tumour-intrinsic metabolic plasticity and redox balance predominate, with microbial and host-derived metabolites assuming relevance when they modulate lipid remodelling and ferroptotic vulnerability. Interpretation is constrained by the intrinsically low biomass of urine and prostate tissue. Robust inference therefore requires quantitative anchoring, orthogonal validation and explicit separation of association from causality. Translational progress is most likely to emerge from calibrated measurement and stage-aware modulation rather than indiscriminate ecological manipulation. By integrating mechanistic, spatial and clinical evidence, this Review proposes a stage-aware framework for the gut-urinary-prostatic axis and delineates when microbial and metabolite signalling meaningfully conditions prostate disease biology-and when it does not.

Acquired or innate lack of response to standard HER2-targeted therapies remains a clinical issue in patients with HER2-positive breast cancer. Here, we investigated the role of the cannabinoid CB2 receptor (CB2R) in trastuzumab resistance. In human breast cancer samples, a decreased expression of HER2-CB2R heterodimers following neoadjuvant treatment, due to CB2R downregulation, was linked to poor long-term outcomes. Using various preclinical models, we demonstrate that CB2R drives trastuzumab resistance. Mechanistically, CB2R loss enabled cancer cells to evade antitumor IFN-γ signaling while promoting a shift from HER2-CB2R to HER2-EGFR heterodimers, thus reducing dependence on HER2 and increasing reliance on EGFR-mediated pathways. Moreover, EGFR inhibition restored trastuzumab sensitivity. In summary, we reveal an unprecedented role for CB2R as a key regulator of oncogenic and immune signaling in response to anti-HER2 therapy and its potential as a predictive biomarker of therapeutic efficacy. We also propose dual HER2/EGFR targeting and non-CB2R-selective cannabinoid therapies as potential strategies to overcome CB2R-mediated trastuzumab resistance. Together, these findings position the endocannabinoid system as a pivotal and actionable node to elucidate, anticipate, and counteract resistance to HER2-targeted therapies.

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.

Aberrant alternative polyadenylation (APA) and alternative splicing (AS) contribute to numerous diseases, including cancer; however, their coordinated roles in ovarian cancer remain poorly understood. Here, we investigated CPSF7, an APA factor markedly upregulated in ovarian cancer and associated with poor prognosis. Silencing CPSF7 suppressed proliferation, migration, and invasion of ovarian cancer cells, while antisense oligonucleotides (ASOs) targeting CPSF7 reduced tumor growth in a patient‑derived xenograft (PDX) model. Mechanistically, knockdown of the splicing factor SNRPD2 induced exon 4 skipping in CPSF7 pre‑mRNA. Loss of exon 4 disrupted the RNA recognition motif (RRM) domain essential for CPSF7‑mediated pre‑mRNA cleavage and polyadenylation, and introduced premature termination codons (PTCs) that generated noncoding transcripts subject to nonsense‑mediated decay (NMD), thereby reducing CPSF7 expression. Thus, efficient splicing mediated by SNRPD2 is crucial for sustaining high CPSF7 levels in ovarian cancer cells. Functional assays showed that CPSF7 knockdown reduced proliferation and metastatic potential in cells with elevated SNRPD2, suggesting that CPSF7 is a key mediator of SNRPD2-driven oncogenesis. Moreover, CPSF7 governed specific APA events to maintain transcript stability, with UBE2K identified as a critical downstream target. CPSF7 preferentially bound distal polyadenylation signals (PASs) within the predominant UBE2K transcript (UBE2K-201), thereby increasing its mRNA stability and maintaining high functional UBE2K expression. Collectively, these findings reveal that AS and APA are interconnected in ovarian cancer via the SNRPD2-CPSF7-UBE2K axis, which drives disease progression and represents a promising target for therapeutic intervention.

Development of castration resistance and distant metastasis remain two major clinical challenges in prostate cancer (PCa) treatment. By analyzing multiple public cancer datasets, we found that ribosomal protein S15 (RPS15) is overexpressed in PCa and related to its metastasis. Beyond its canonical role as a structural component of the ribosome, emerging evidence has highlighted the extraribosomal functions of RPS15 in disease progression. Our study demonstrates that RPS15 significantly promotes proliferation and migration in PCa through the establishment of RPS15 knockdown cells and xenograft models. Mechanistically, RPS15 interacts with the functional domain of DExD-box helicase 21 (DDX21) and facilitates the binding of DDX21 to the transcription start region of stearoyl-CoA desaturase-1 (SCD1), thereby enhancing its transcriptional activity and protein expression to drive the growth, ferroptosis-resistance, and metastasis of PCa cells. Moreover, analysis of clinical samples revealed that RPS15, DDX21, and SCD1 are concomitantly upregulated and exhibit strong positive correlations in PCa tissues. Collectively, our findings uncover the significance of the RPS15-DDX21-SCD1 axis in PCa development, expanding the understanding of noncanonical functions of ribosomal proteins and providing new insights for PCa management.

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.

Prostate cancer (PC) is one of the most common malignancies in men, and the emergence of androgen receptor-low/negative castration-resistant PC (ARL/- CRPC) following androgen receptor signaling inhibitor (ARSI) therapy remains a critical clinical challenge. The RNA-binding protein DEAD-box helicase 3 X-linked (DDX3X) has been implicated in the translational regulation of androgen receptor (AR) mRNA; however, the underlying binding mechanisms are not well defined. Here, we show that DDX3X colocalizes with AR mRNA in ARL/- CRPC cells and selectively recognizes non-canonical RNA G-quadruplex (rG4) motifs within the sequence of AR mRNA. RNA immunoprecipitation sequencing (RIP-seq) revealed enrichment of DDX3X-AR mRNA interactions in ARL/- CRPC cells. Fluorescence imaging confirmed the colocalization of DDX3X and AR mRNA within cytoplasmic granules, and biochemical assays confirmed the ability of selected AR mRNA fragments to form rG4 structures bound by DDX3X. Proteomic profiling of DDX3X-Ras GTPase-activating protein-binding protein 1 (G3BP1) complexes identified several RNA-binding proteins, including IGF2BP1, PUM2, and UBAP2, which may act as candidate cofactors. Together, these findings shed light on the interaction between AR mRNA and DDX3X and identify putative protein partners, offering insights into future therapeutic strategies.

Myofibroblastic cancer-associated fibroblasts (myoCAFs) represent a crucial stromal cell subpopulation associated with tumor growth, relapse, and metastasis. In this study, we identify a noncanonical mechanism through which head and neck cancer cells regulate myoCAF activation. Co-culture with tumor organoids promoted the expression of cytokine interaction-related genes and myoCAF phenotypic markers in paracancerous fibroblasts (PFs). Cytokine and tissue array analyses revealed that upregulation of colony-stimulating factor-2 (CSF2) in tumor cells correlated with overexpression of nicotinamide N-methyltransferase (NNMT) in CAFs. Notably, CSF2 treatment enhanced myoCAF properties in a NNMT-dependent manner, while NNMT overexpression remained largely unaffected by transforming growth factor-β (TGF-β). In both assembled organoid and xenograft models, tumor growth was reduced when either CSF2 in cancer cells or CSF2 receptor subunit CSF2RA in CAFs was knocked down. Mechanistically, CSF2 induced FOS phosphorylation at Ser32, promoting nuclear translocation of phosphorylated FOS (p-FOS) to regulate NNMT transcription. In drug screening assays, CSF2 blockade partially overcame resistance to TGF-β inhibition. These findings establish the CSF2/FOS/NNMT axis as a TGF-β-independent pathway driving myoCAF activation.