Pancreatic ductal adenocarcinoma remains among the deadliest malignancies worldwide, and effective therapies are still lacking. Actinomycetota are among the richest microbial sources of bioactive secondary metabolites, and three agents in clinical use against pancreatic malignancy derive from them - streptozotocin, everolimus and doxorubicin - though all three are indicated for neuroendocrine rather than ductal tumors. This review provides a critical narrative synthesis of Actinomycetota-derived metabolites evaluated in pancreatic cancer models, with every potency value re-derived from the primary literature and interpreted alongside assay conditions and available mechanistic and in vivo evidence.

Oncolytic bacteria are microorganisms with cytotoxic activity capable of lysing cancer cells while simultaneously activating both innate and adaptive immune responses to exert anti-tumor effects. However, the innate immune activation targeting oncolytic bacteria within the tumor microenvironment (TME) is a limiting factor. Here we find that the CD11b-targeting agonist GB1275 can modulate bacteria-immune interaction and inhibit the infiltration of CD11b[+] innate immune cells such as neutrophils and macrophages, thereby suppressing the antimicrobial immune defenses in the TME in mice. This then avoids the clearance of oncolytic bacteria and increases the efficacy of bacteria-mediated tumor immunotherapy. Furthermore, the gemcitabine-loaded bacteria combined with GB1275 treatment activate innate immune responses in tumor, as mediated by Toll-like receptors (TLR), NOD-like receptors (NLR) and cGAS-STING pathways, while simultaneously enhancing dendritic cell (DC)-dependent antigen cross-presentation; this then upregulates the adaptive anti-tumor immune response and inhibits the growth of both subcutaneous and in situ pancreatic cancers in mouse tumor models. Our results therefore demonstrate that modulating innate immune responses while subsequently strengthening adaptive immune activation can significantly improve the efficacy of bacteria-mediated tumor immunotherapy.

Chemotherapy remains a cornerstone of cancer treatment, yet therapeutic resistance continues to limit durable clinical responses. MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression that orchestrate diverse cellular processes implicated in drug sensitivity and resistance. However, the contribution of miRNA regulatory networks to chemotherapy response has not been systematically characterized using clinical patient cohorts. Here we present DrugMiR, an integrative multi-omics modeling framework that integrates drug response-associated miRNAs with experimentally validated target genes to identify regulatory signatures predictive of chemotherapy response. Using 1015 patient samples from The Cancer Genome Atlas, we identified differentially expressed miRNAs (DEmiRs) associated with response to five widely used chemotherapeutic agents (cisplatin, carboplatin, gemcitabine, paclitaxel, and fluorouracil) and constructed predictive models using multiple machine learning algorithms. DrugMiR achieved robust predictive performance, particularly for platinum-based therapies, with area under the receiver operating characteristic curves of 0.81 for cisplatin and 0.79 for carboplatin. Integration of validated miRNA targets consistently improved predictive performance while substantially enhancing biological interpretability. Integrative network and pathway analyses identified recurrent miRNA-target regulatory programs shared across chemotherapy cohorts, particularly involving the miR-200 family and target genes such as BMP2, ITGA3, EGFR, FGFR1, MET, and IL6, implicating growth factor signaling, focal adhesion, extracellular matrix remodeling, and adaptive survival pathways in chemotherapy response. Together, these findings establish patient-derived miRNA-target regulatory signatures as robust predictors of chemotherapy response and provide a multi-omics framework for elucidating molecular mechanisms underlying therapeutic sensitivity and resistance across diverse cancer types.

Pancreatic adenocarcinoma with distant metastases is associated with a poor prognosis, and exceptionally durable responses to systemic chemotherapy are uncommon. We report a rare case of pancreatic adenocarcinoma with radiologically suspected multiple liver metastases that achieved a prolonged response to first-line tegafur/gimeracil/oteracil (S-1) monotherapy. A 76-year-old man with a history of cerebral infarction and diabetes mellitus was referred to our department because of rapidly worsening diabetes. Imaging revealed an approximately 3-cm pancreatic head tumor and multiple hepatic lesions highly suspicious for metastases. Serum carbohydrate antigen 19-9 (CA19-9) was markedly elevated. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of the pancreatic head tumor demonstrated adenocarcinoma on both cytological and histopathological examinations. Gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) was proposed; however, the patient preferred oral treatment. Considering his age, quality of life, and treatment preference, S-1 monotherapy was initiated at 100 mg/day on a 2-week-on/2-week-off schedule. Following initiation of S-1, the pancreatic and hepatic lesions progressively regressed, accompanied by rapid normalization of CA19-9. By approximately 14 months after treatment initiation, the previously identifiable pancreatic primary tumor and hepatic lesions were no longer clearly visualized on computed tomography (CT). S-1 monotherapy was continued with few interruptions, and no apparent radiological progression was documented for approximately 47 months. Approximately two and a half months after the last CT showing no apparent progression, the patient developed fever and dyspnea. CT demonstrated newly developed bilateral ground-glass and interstitial pulmonary opacities, along with new-onset ascites, without evidence of regrowth of the pancreatic or hepatic lesions. S-1-induced interstitial lung disease (ILD) was clinically suspected; however, occult malignant progression could not be definitively excluded. His respiratory condition deteriorated despite treatment, and he subsequently died. This case demonstrates that an exceptionally durable response may rarely occur with first-line S-1 monotherapy even in pancreatic adenocarcinoma with radiologically suspected metastatic disease.

Systemic therapy for biliary tract cancer (BTC) has evolved substantially over the past two decades. Gemcitabine plus cisplatin was established as the global standard first-line regimen, followed by further optimization through alternative doublets, intensified triplet chemotherapy, and the recent introduction of immune checkpoint inhibitor-based combinations. In Japan, pivotal clinical trials have played a valuable role in refining treatment strategies, including the establishment of gemcitabine plus S-1, gemcitabine, cisplatin, plus S-1, and adjuvant S-1 after curative resection. Beyond cytotoxic chemotherapy, molecular targeted therapy and tumor-agnostic approaches have expanded treatment options for selected patients in the second-line and later-line settings. Actionable alterations such as FGFR2 fusions, IDH1 mutations, HER2 amplification, microsatellite instability-high status, and other rare genomic events enable precision medicine approaches with meaningful clinical benefit. Despite these advances, prognosis remains poor for many patients with BTC. Ongoing efforts to optimize treatment sequencing, refine perioperative strategies, and integrate comprehensive molecular profiling are expected to further improve outcomes. Continued generation of high-quality clinical evidence and international collaboration will be essential to advance the management of BTC.