Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, and gemcitabine (GEM) resistance is a major contributor to its poor clinical outcomes, generating an urgent need for novel therapeutic strategies targeting tumor proliferation and tumor-cell-intrinsic malignant signaling. This study aimed to investigate the synergistic anti-PDAC efficacy and underlying mechanism of cepharanthine (CEP) combined with GEM. A series of in vitro and in vivo experiments were performed to evaluate the antitumor activity, synergistic effect and preliminary in vivo safety of the CEP-GEM combination. Bioinformatics analysis coupled with experimental validation was applied to dissect the underlying mechanisms. The results demonstrated that CEP produced marked synergistic effects with GEM to suppress PDAC growth both in vitro and in vivo. Mechanistic investigations revealed that CEP blocked the PI3K/AKT/mTOR pathway and reduced tumor-cell-intrinsic PD-1/PD-L1 levels, thereby facilitating tumor-cell apoptosis, restraining cell migration and invasion, and sensitizing GEM-relatively insensitive AsPC-1 cells to GEM. Under our experimental conditions, no obvious histopathological injury or prominent systemic toxicity was observed. In conclusion, this work provides preclinical evidence showing that the CEP-GEM combination exerts anti-tumor activity via dual-pathway suppression in PDAC cells, and supports further translational research for PDAC.

Intravesical Bacillus Calmette-Guérin (BCG) remains the standard adjuvant treatment for intermediate- and high-risk non-muscle-invasive bladder cancer. However, 30-50% of patients fail to respond or experience recurrence within two years, while clinical and pathological risk models have limited accuracy in predicting individual response. This narrative review summarizes molecular classifications and candidate biomarkers associated with BCG response and assesses their potential clinical utility, based on a focused search of PubMed, Scopus, and Web of Science through July 2026, supplemented by ClinicalTrials.gov, regulatory documents, and current guidelines. Transcriptomic classifications, including UROMOL2021, BCG Response Subtypes (BRS), MSP888, and subtypes defined in stage T1 disease, identify tumor phenotypes associated with differences in recurrence, progression, and outcomes after BCG. BRS3 is characterized by basal-squamous and immunosuppressive features and is associated with shorter recurrence-free and progression-free survival. Genomic alterations, including FGFR3 and TERT promoter mutations and APOBEC signatures; DNA methylation markers such as GATA2, TBX3, and GPR158; and tumor microenvironment features, including regulatory T cells, exhausted CD8+ T cells, and PD-L1 expression, have been associated with outcomes in individual cohorts but remain unvalidated as treatment-specific predictors. Bladder-preserving options for BCG-unresponsive disease include pembrolizumab, nadofaragene firadenovec, nogapendekin alfa inbakicept-pmln with BCG, and the gemcitabine intravesical system. Randomized trials adding checkpoint inhibition to BCG in BCG-naive disease have reported inconsistent results. No molecular biomarker is currently validated for treatment selection. Molecular profiling remains investigational and may complement, but not replace, established clinical risk assessment. Clinical implementation requires prospective biomarker-stratified trials with standardized definitions, assays, and endpoints.

Chemoresistance is a principal cause of treatment failure in bladder cancer (BLCA), yet the mechanisms that actively maintain resistance remain poorly defined. Gemcitabine (GEM) resistance is classically attributed to impaired drug uptake via human equilibrative nucleoside transporter 1 (hENT1) and activation of pro-survival cell signaling pathways. However, these mechanisms do not explain how resistance is stably sustained over time. Here we uncover an autophagy-dependent pathway that maintains GEM chemoresistance, in which nucleolin (NCL) shields the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) from microtubule-associated protein 1 light chain 3 beta (LC3B)-mediated autophagic degradation. Consequently, NCL-mediated stabilization of PTBP1 maintains glycolytic reprogramming in GEM-resistant BLCA cells, whereas NCL additionally promotes anti-apoptotic signaling. Notably, PTBP1 is enriched and preserved as a functional and surface-accessible dependency through NCL-mediated evasion of autophagic degradation. To exploit this vulnerability, we developed a monovalent dual-target DNA aptamer, SWL-3, that undergoes preferential internalization through surface-accessible PTBP1 while also binding NCL, enabling selective recognition of xenograft tumors in vivo and clinical BLCA specimens in vitro. By bypassing classical hENT1-dependent drug uptake, site-specifically conjugated SWL-3G achieves efficient intracellular drug accumulation and selectively reduces the viability of GEM-resistant, PTBP1-enriched cells. Together, these findings reveal NCL-mediated protein shielding from autophagic degradation as a mechanism that sustains GEM resistance and establish these resistance-maintaining dependencies as actionable targets for precision therapy in refractory disease.

Proteasome is an established therapeutic target in cancer, and proteasome inhibitors (PIs) such as bortezomib (BTZ) are clinically used for hematologic malignancies, including multiple myeloma. Although PIs have also been evaluated in solid tumors, their clinical efficacy has been limited. We therefore sought to develop a strategy to enhance PI efficacy using gemcitabine/cisplatin (GC)-resistant bladder cancer cells as a model of refractory solid cancer. One mechanism that limits PI efficacy is the nuclear factor erythroid 2-related factor 1 (NRF1, NFE2L1)-mediated proteasome bounce-back response, which restores proteasome capacity after inhibition. Because DNA damage-inducible 1 homolog 2 (DDI2)-mediated processing is required for NRF1 activation, we examined whether nelfinavir (NFV), a reported DDI2 inhibitor, could enhance BTZ sensitivity. GC-resistant T24GC cells exhibited increased basal proteasome activity, cross-resistance to PIs, and a stronger NRF1-mediated bounce-back response than parental T24 cells. NFV significantly enhanced BTZ-induced cytotoxicity and apoptosis in T24GC cells. Unexpectedly, NFV did not suppress the bounce-back response but instead further enhanced NRF1 activation in T24GC cells, possibly reflecting pharmacological actions of NFV beyond DDI2 inhibition. These findings identify enhanced NRF1-mediated proteasome adaptation as a feature of GC resistance and highlight the need for highly selective DDI2 inhibitors to evaluate DDI2-NRF1 targeting as a strategy to improve PI efficacy in drug-resistant solid cancers.

This letter comments on a recent review of theranostic lipid nanocarriers for pancreatic ductal adenocarcinoma, identifying three areas of concern in the evidence base. First, the 211-item reference list contains multiple duplicated citations listed under separate numbers with identical content (for example, refs. 6/8, 9/21, 55/89, 106/117, 132/143), a recurring pattern suggesting that the bibliography was not fully verified before submission. Second, Table 6 cites reference markers "[639]" and "[640]" for the NanoSMART and NBTXR3 trials, numbers that exceed the 211-entry reference list and appear to be residual artifacts from a source document with a different numbering scheme. Third, the review reports that NC-6004 (a micellar cisplatin formulation) has completed a phase III trial in combination with gemcitabine but omits the trial's outcome, despite the review's broader argument for the translational viability of lipid- and micelle-based nanocarriers and its extended discussion of nab-paclitaxel as a successful precedent. Reporting this outcome, favorable or not, alongside existing precedents, would allow readers to weigh the review's central claim against the complete record of late-stage clinical testing. While the review offers a valuable catalogue of nanocarrier platforms and regulatory precedents, these issues warrant correction before the citation base is treated as fully reliable.

Locoregional pathological complete response with concurrent radiologic metabolic remission following palliative gemcitabine-carboplatin chemotherapy in young, low-grade metastatic triple-negative breast cancer patient suggests potential chemosensitivity in select advanced cases, warranting further clinical investigation.

Claims that glucose-containing anticancer infusions 'feed cancer' conflate a transient pharmaceutical carrier with chronic dysglycaemia and assume that glucose uptake equals tumour growth. We developed GLUCOSE-ONC, a multistream critical review separating direct systemic carrier comparisons, acute human glycaemia, parenteral nutrition as a high-exposure boundary, chronic dysglycaemia, and translational glucose-drug interactions. Four reproducible PubMed searches yielded 1,077 unique records; chronic dysglycaemia was handled as contextual evidence, and the clinically relevant set was curated with explicit causal-distance rules. Only one randomised systemic carrier comparison was identified: 5% glucose reduced gemcitabine vascular pain versus saline, but progression and survival were not measured. Dextrose-based hyperthermic intraperitoneal chemotherapy produced marked hyperglycaemia and inconsistent perioperative outcomes, but its large heated intraperitoneal exposure is not transportable to routine systemic carriers. Parenteral-nutrition trials, despite much larger and repeated nutrient exposure, showed mixed survival findings and no consistent neoplastic-acceleration pattern; infection and catheter effects contributed to net harm. Translational findings were bidirectional: high glucose induced resistance in some models but sensitised pancreatic and hepatocellular models, whereas glucose deprivation also induced resistance in selected endometrial and ovarian models. A 100-500 mL 5% dextrose bag contains 5-25 g; at 70 kg, 25 g over 2 h is 2.98 mg/kg/min, a transient flux subject to endogenous-production and disposal feedback. Standard glucose-containing infusion should not be conflated with chronic hyperglycaemia. Available evidence does not support the claim that transient carrier-level glucose exposure accelerates cancer progression, although direct outcome studies remain insufficient to prove exact equivalence.